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1
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Mitra R, Pentland K, Kolev S, Eden M, Levine E, Oakes JM, Ebong EE. Co-therapy with S1P and heparan sulfate derivatives to restore endothelial glycocalyx and combat pro-atherosclerotic endothelial dysfunction. Life Sci 2025; 377:123662. [PMID: 40280298 DOI: 10.1016/j.lfs.2025.123662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 04/14/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
AIMS Endothelial cell (EC) glycocalyx (GCX) shedding from disturbed blood flow and chemical factors leads to low-density lipoprotein infiltration, reduced nitric oxide synthesis, vascular dysfunction and atherosclerosis. This study evaluates a therapy combining sphingosine-1-phosphate (S1P) and heparin (heparan sulfate derivative). We hypothesized that heparin/S1P co-treatment repairs mechanically damaged EC GCX in disturbed flow (DF) regions and restores anti-atherosclerotic mechanotransduction to treat cardiovascular disease. MATERIALS AND METHODS We used a parallel-plate flow chamber to simulate flow conditions in vitro and a partial carotid ligation mouse model to mimic DF in vivo. Heparin and albumin-bound S1P were administered to assess their reparative effects on the endothelial GCX. Fluorescent staining, confocal microscopy, and ultrasound evaluated endothelial cell function and endothelial-dependent vascular function. Barrier functionality was assessed via macrophage uptake. Heparin/S1P mechanism-of-action insights were gained through fluid dynamics simulations and staining of GCX synthesis enzyme and S1P receptor. Statistical analyses validated the results. KEY FINDINGS The in vitro data showed that heparin/S1P therapy improves DF-conditioned ECs by restoring GCX and elevating vasodilator eNOS (endothelial-type nitric oxide synthase) expression. In vivo studies confirmed GCX degradation, vessel inflammation, hyperpermeability, and wall thickening in the mouse model's partially ligated left carotid artery. Heparin/S1P treatment restored GCX thickness and coverage, reduced inflammation and hyperpermeability, and inhibited vessel wall thickening. SIGNIFICANCE This work introduces a new approach to regenerating the EC GCX and restoring its function in ECs under DF conditions, offering a groundbreaking solution for preventing cardiovascular diseases like atherosclerosis.
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Affiliation(s)
- Ronodeep Mitra
- Department of Chemical Engineering, Northeastern University, Boston, MA, United States
| | - Kaleigh Pentland
- Department of Bioengineering, Northeastern University, Boston, MA, United States
| | - Svilen Kolev
- Department of Chemical Engineering, Northeastern University, Boston, MA, United States
| | - Matthew Eden
- Department of Bioengineering, Northeastern University, Boston, MA, United States
| | - Erel Levine
- Department of Bioengineering, Northeastern University, Boston, MA, United States
| | - Jessica M Oakes
- Department of Bioengineering, Northeastern University, Boston, MA, United States
| | - Eno E Ebong
- Department of Chemical Engineering, Northeastern University, Boston, MA, United States; Department of Bioengineering, Northeastern University, Boston, MA, United States; Department of Neuroscience, Albert Einstein College of Medicine, NY, New York, United States.
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2
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Li Y, Fu BM. A Cost-Effective and Easy to Assemble 3D Human Microchannel Blood-Brain Barrier Model and Its Application in Tumor Cell Adhesion Under Flow. Cells 2025; 14:456. [PMID: 40136705 PMCID: PMC11941619 DOI: 10.3390/cells14060456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 03/14/2025] [Accepted: 03/18/2025] [Indexed: 03/27/2025] Open
Abstract
By utilizing polydimethylsiloxane (PDMS), collagen hydrogel, and a cell line for human cerebral microvascular endothelial cells, we produced a 3D microchannel blood-brain barrier (BBB) model under physiological flow. This 3D BBB has a circular-shaped cross-section and a diameter of ~100 μm, which can properly mimic the cerebral microvessel responsible for material exchange between the circulating blood and brain tissue. The permeability of the 3D microchannel BBB to a small molecule (sodium fluorescein with a molecular weight of 376) and that to a large molecule (Dex-70k) are the same as those of rat cerebral microvessels. This 3D BBB model can replicate the effects of a plasma protein, orosomucoid, a cytokine, vascular endothelial growth factor (VEGF), and an enzyme, heparinase III, on either rat cerebral or mesenteric microvessesels in terms of permeability and the modulation of glycocalyx (heparan sulfate). It can also replicate the adhesion of a breast cancer cell, MDA-MB-231, in rat mesenteric microvessels under no treatment or treatments with VEGF, orosomucoid, and heparinase III. Because of difficulties in accessing human cerebral microvessels, this inexpensive and easy to assemble 3D human BBB model can be applied to investigate BBB-modulating mechanisms in health and in disease and to develop therapeutic interventions targeting tumor metastasis to the brain.
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Affiliation(s)
| | - Bingmei M. Fu
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA;
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3
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Wang J, Ma L, Fang Y, Ye T, Li H, Lan P. Factors influencing glycocalyx degradation: a narrative review. Front Immunol 2025; 15:1490395. [PMID: 39885987 PMCID: PMC11779607 DOI: 10.3389/fimmu.2024.1490395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 12/30/2024] [Indexed: 02/01/2025] Open
Abstract
The glycocalyx is a layer of villus-like structure covering the luminal surface of vascular endothelial cells. Damage to the glycocalyx has been proven linked to the development of many diseases. However, the factors that promote damage to the glycocalyx are not fully elaborated. This review summarizes factors leading to the reduction of the glycocalyx in detail, including inflammatory factors, ischemia-reperfusion, oxidative stress, lipids, glucose, high sodium, female sex hormones and others. Additionally, the mechanisms underlying its degradation are discussed. To better prevent and treat related diseases induced by glycocalyx degradation, it is a meaningful measure to avoid these factors.
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Affiliation(s)
- Jing Wang
- Department of Cardiology, Nanning Hospital of Traditional Chinese Medicine, Nanning, Guangxi, China
| | - Lan Ma
- Department of Neurology, Wenzhou Traditional Chinese Medicine (TCM) Hospital of Zhejiang Chinese Medical University, Wenzhou, Zhejiang, China
| | - Yu Fang
- Department of Cardiology, Nanning Hospital of Traditional Chinese Medicine, Nanning, Guangxi, China
| | - Tengteng Ye
- Department of Cardiology, Nanning Hospital of Traditional Chinese Medicine, Nanning, Guangxi, China
| | - Hongbo Li
- Department of Cardiology, Nanning Hospital of Traditional Chinese Medicine, Nanning, Guangxi, China
| | - Peng Lan
- Department of Cardiology, Nanning Hospital of Traditional Chinese Medicine, Nanning, Guangxi, China
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Batinac T, Batičić L, Kršek A, Knežević D, Marcucci E, Sotošek V, Ćurko-Cofek B. Endothelial Dysfunction and Cardiovascular Disease: Hyperbaric Oxygen Therapy as an Emerging Therapeutic Modality? J Cardiovasc Dev Dis 2024; 11:408. [PMID: 39728298 DOI: 10.3390/jcdd11120408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 12/28/2024] Open
Abstract
Maintaining the physiological function of the vascular endothelium and endothelial glycocalyx is crucial for the prevention of cardiovascular disease, which is one of the leading causes of morbidity and mortality worldwide. Damage to these structures can lead to atherosclerosis, hypertension, and other cardiovascular problems, especially in individuals with risk factors such as diabetes and obesity. Endothelial dysfunction is associated with ischemic disease and has a negative impact on overall cardiovascular health. The aim of this review was to comprehensively summarize the crucial role of the vascular endothelium and glycocalyx in cardiovascular health and associated thrombo-inflammatory conditions. It highlights how endothelial dysfunction, influenced by factors such as diabetes, chronic kidney disease, and obesity, leads to adverse cardiovascular outcomes, including heart failure. Recent evidence suggests that hyperbaric oxygen therapy (HBOT) may offer therapeutic benefits in the treatment of cardiovascular risk factors and disease. This review presents the current evidence on the mechanisms by which HBOT promotes angiogenesis, shows antimicrobial and immunomodulatory effects, enhances antioxidant defenses, and stimulates stem cell activity. The latest findings on important topics will be presented, including the effects of HBOT on endothelial dysfunction, cardiac function, atherosclerosis, plaque stability, and endothelial integrity. In addition, the role of HBOT in alleviating cardiovascular risk factors such as hypertension, aging, obesity, and glucose metabolism regulation is discussed, along with its impact on inflammation in cardiovascular disease and its potential benefit in ischemia-reperfusion injury. While HBOT demonstrates significant therapeutic potential, the review also addresses potential risks associated with excessive oxidative stress and oxygen toxicity. By combining information on the molecular mechanisms of HBOT and its effects on the maintenance of vascular homeostasis, this review provides valuable insights into the development of innovative therapeutic strategies aimed at protecting and restoring endothelial function to prevent and treat cardiovascular diseases.
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Affiliation(s)
- Tanja Batinac
- Department of Clinical Medical Sciences I, Faculty of Health Studies, University of Rijeka, Viktora Cara Emina 2, 51000 Rijeka, Croatia
- Department of Underwater and Hyperbaric Medicine, Clinical Hospital Center Rijeka, Tome Strižića 3, 51000 Rijeka, Croatia
| | - Lara Batičić
- Department of Medical Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia
| | - Antea Kršek
- Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia
| | - Danijel Knežević
- Department of Anesthesiology, Reanimatology, Emergency and Intensive Care Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia
| | - Emanuela Marcucci
- Department of Clinical Medical Sciences I, Faculty of Health Studies, University of Rijeka, Viktora Cara Emina 2, 51000 Rijeka, Croatia
- Department of Underwater and Hyperbaric Medicine, Clinical Hospital Center Rijeka, Tome Strižića 3, 51000 Rijeka, Croatia
| | - Vlatka Sotošek
- Department of Clinical Medical Sciences I, Faculty of Health Studies, University of Rijeka, Viktora Cara Emina 2, 51000 Rijeka, Croatia
- Department of Anesthesiology, Reanimatology, Emergency and Intensive Care Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia
| | - Božena Ćurko-Cofek
- Department of Physiology, Immunology and Pathophysiology, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia
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Ye W, Xu S, Liu Y, Ye Z. Role of endothelial glycocalyx in central nervous system diseases and evaluation of the targeted therapeutic strategies for its protection: a review of clinical and experimental data. Rev Neurosci 2024; 35:839-853. [PMID: 39034663 DOI: 10.1515/revneuro-2024-0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 05/22/2024] [Indexed: 07/23/2024]
Abstract
Central nervous system (CNS) diseases, such as stroke, traumatic brain injury, dementia, and demyelinating diseases, are generally characterized by high morbidity and mortality, which impose a heavy economic burden on patients and their caregivers throughout their lives as well as on public health. The occurrence and development of CNS diseases are closely associated with a series of pathophysiological changes including inflammation, blood-brain barrier disruption, and abnormal coagulation. Endothelial glycocalyx (EG) plays a key role in these changes, making it a novel intervention target for CNS diseases. Herein, we review the current understanding of the role of EG in common CNS diseases, from the perspective of individual pathways/cytokines in pathophysiological and systematic processes. Furthermore, we emphasize the recent developments in therapeutic agents targeted toward protection or restoration of EG. Some of these treatments have yielded unexpected pharmacological results, as previously unknown mechanisms underlying the degradation and destruction of EG has been brought to light. Furthermore, the anti-inflammatory, anticoagulative, and antioxidation effects of EG and its protective role exerted via the blood-brain barrier have been recognized.
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Affiliation(s)
- Weihao Ye
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Shang Xu
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Ying Liu
- Department of Rehabilitation Medicine, 117742The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Ziming Ye
- Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
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Mitra R, Pentland K, Kolev S, Eden M, Levine E, Oakes JM, Ebong EE. Co-Therapy with S1P and Heparan Sulfate Derivatives to Restore Endothelial Glycocalyx and Combat Pro-Atherosclerotic Endothelial Dysfunction. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.06.622347. [PMID: 39574692 PMCID: PMC11581019 DOI: 10.1101/2024.11.06.622347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Endothelial cell (EC) glycocalyx (GCX) shedding due to disturbed blood flow and chemical factors leads to low-density lipoprotein infiltration and reduced nitric oxide synthesis, causing vascular dysfunction and atherosclerosis. This study evaluates a novel therapy combining sphingosine-1-phosphate (S1P) and heparin (heparan sulfate derivative). We hypothesized that heparin/S1P would repair mechanically damaged EC GCX in disturbed flow (DF) regions and restore anti-atherosclerotic mechanotransduction function, addressing cardiovascular disease. We used a parallel-plate flow chamber to simulate flow conditions in vitro and a partial carotid ligation mouse model to mimic DF in vivo. Heparin and albumin-bound S1P were administered to assess their reparative effects on the endothelial GCX. Immunocytochemistry, fluorescent staining, confocal microscopy, cellular alignment studies, and ultrasound were performed to evaluate EC function and endothelial-dependent vascular function. Barrier functionality was assessed via macrophage uptake. Heparin/S1P mechanism-of-action insights were gained through fluid dynamics simulations and staining of GCX synthesis enzyme as well as S1P receptor. Statistical analyses validated results. In vitro data showed that heparin/S1P therapy improves the function of DF-conditioned ECs by restoring EC GCX and promoting EC alignment and elevated vasodilator eNOS (endothelial-type nitric oxide synthase) expression. The in vivo studies confirmed GCX degradation, increased vessel inflammation and hyperpermeability, and vessel wall thickening in the partially ligated left carotid artery. Heparin/S1P treatment restored GCX in the left carotid artery, enhancing GCX thickness and coverage of the blood vessel wall. This work advances a new approach to regenerating the EC GCX and restoring its function in ECs under DF conditions.
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Harris D, Groß M, Staebler S, Ebert R, Seibel J, Boßerhoff AK. Modifying the Glycocalyx of Melanoma Cells via Metabolic Glycoengineering Using N-Acetyl-d-glucosamine Analogues. Cells 2024; 13:1831. [PMID: 39594580 PMCID: PMC11592549 DOI: 10.3390/cells13221831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 11/01/2024] [Accepted: 11/04/2024] [Indexed: 11/28/2024] Open
Abstract
Tumor cells are decorated with aberrant glycan structures on cell surfaces. It is well known that the glycocalyx serves as a main cellular regulator, although its role in cancer is still not completely understood. Over recent decades, several non-natural monosaccharides carrying clickable groups have been introduced in melanoma cells. This technique, called Metabolic Glycoengineering (MGE), opens up the possibility of altering the cell's glycocalyx via click chemistry using a two-step approach. This study expands the field of MGE by showing the successful metabolic incorporation of novel alternative artificial glucosamine derivatives. The latter were either deoxygenated or blocked by methyl ether in position 4 to generate deficient glycosylation patterns, while being extended by an alkyne to enable click chemistry as a one-step approach. As a result, we observed a reduced proliferation rate of melanoma cells. Furthermore, using a lectin array, the decrease in high mannose epitopes was observed. In summary, the successful use of alternative artificial glucosamine derivatives enabled a significant alteration in the glycocalyx, consequently influencing cell behavior.
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Affiliation(s)
- David Harris
- Institute of Biochemistry, Friedrich Alexander University Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany; (D.H.); (S.S.)
| | - Marcel Groß
- Institute of Organic Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, 97074 Würzburg, Germany;
| | - Sebastian Staebler
- Institute of Biochemistry, Friedrich Alexander University Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany; (D.H.); (S.S.)
| | - Regina Ebert
- Department of Musculoskeletal Tissue Regeneration, Orthopedic Clinic König-Ludwig Haus, Julius-Maximilians-University of Würzburg, Friedrich-Bergius-Ring 15, 97076 Würzburg, Germany;
| | - Jürgen Seibel
- Institute of Organic Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, 97074 Würzburg, Germany;
| | - Anja Katrin Boßerhoff
- Institute of Biochemistry, Friedrich Alexander University Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany; (D.H.); (S.S.)
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8
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Triebold C, Barber J. The effect of the endothelial surface layer on cell-cell interactions in microvessel bifurcations. Biomech Model Mechanobiol 2024; 23:1695-1721. [PMID: 38847968 DOI: 10.1007/s10237-024-01863-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 05/19/2024] [Indexed: 09/28/2024]
Abstract
Red blood cells (RBCs) carry oxygen and make up 40-45% of blood by volume in large vessels down to 10% or less in smaller capillaries. Because of their finite size and large volume fraction, they are heterogeneously distributed throughout the body. This is partially because RBCs are distributed or partitioned nonuniformly at diverging vessel bifurcations where blood flows from one vessel into two. Despite its increased recognition as an important player in the microvasculature, few studies have explored how the endothelial surface layer (ESL; a vessel wall coating) may affect partitioning and RBC dynamics at diverging vessel bifurcations. Here, we use a mathematical and computational model to consider how altering ESL properties, as can occur in pathological scenarios, change RBC partitioning, deformation, and penetration of the ESL. The two-dimensional finite element model considers pairs of cells, represented by interconnected viscoelastic elements, passing through an ESL-lined diverging vessel bifurcation. The properties of the ESL include the hydraulic resistivity and an osmotic pressure difference modeling how easily fluid flows through the ESL and how easily the ESL is structurally compressed, respectively. We find that cell-cell interaction leads to more uniform partitioning and greatly enhances the effects of ESL properties, especially for deformation and penetration. This includes the trend that increased hydraulic resistivity leads to more uniform partitioning, increased deformation, and decreased penetration. It also includes the trend that decreased osmotic pressure increases penetration.
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Affiliation(s)
- Carlson Triebold
- Department of Mathematical, Information and Computer Sciences, Point Loma Nazarene University, San Diego, USA.
| | - Jared Barber
- Department of Mathematical Sciences, Indiana University Indianapolis, Indianapolis, USA
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Zhang Y, Ma N, Wang L, Liu L, Wang T, Liu H, Qian W. Real-Time Study of the Specific Interactions of Lactoferrin with Mimicked Heparan Sulfate Meshes Using Ordered Porous Layer Interferometry. Anal Chem 2024; 96:14413-14423. [PMID: 38989558 DOI: 10.1021/acs.analchem.4c01808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
Heparan sulfate (HS) meshes within the glycocalyx on cell surfaces have protein recognition ability and have been crucial for gaining insights into vital bioprocesses, such as viral infection, cancer development, and inflammation. The protein recognition ability is determined by the mesh property and compositions of HS, although little attention has been paid to the effect of the mesh property on the recognition. An in-depth specificity study of protein-HS-mesh recognition is essential to illustrate related biological functions. Here, ordered porous layer interferometry is applied to study the interaction behavior between mimicked HS meshes and lactoferrin (LF). Our work aimed at mimicking HS meshes with heparin, a widely used substitute of HS, and analyzing the specific LF-heparin-mesh interaction mechanism by inhibiting the nonspecific interaction in a blended sample. We found that the counterion release-based electrostatic interaction is dominant in the specific LF-heparin-mesh recognition. Furthermore, we detail the contributions of nonspecific and specific interactions to the recognition. We illustrate that the concentrated charge distribution of the proteins appears to be primarily related to this robust, specific recognition.
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Affiliation(s)
- Yu Zhang
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Ning Ma
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Lu Wang
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Liming Liu
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Tianze Wang
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Hao Liu
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Weiping Qian
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
- OPLI (Suzhou) Biotechnology Co., Ltd., New District, Suzhou 215163, China
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Zieliński A, Jasińska-Sumińska K, Bręborowicz A, Kowalska K, Zabel M, Wysocka T, Khalil RA, Raffetto JD, Urbanek T. Changes of the serum properties and its effect on the endothelial cells restoration in patients with chronic venous disease treated with sulodexide. J Vasc Surg Venous Lymphat Disord 2024; 12:101941. [PMID: 38945361 PMCID: PMC11523325 DOI: 10.1016/j.jvsv.2024.101941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Revised: 06/12/2024] [Accepted: 06/16/2024] [Indexed: 07/02/2024]
Abstract
OBJECTIVE Inflammation and endothelial dysfunction are important venous changes in patients with chronic venous disease (CVD). The use of the venoactive drugs remains an important treatment modality for patients with CVD, reducing the severity of the CVD-related symptoms and swelling but also reducing inflammation and protecting endothelial cells. In this research, the effects of the serum obtained from patients with CVD before and after sulodexide treatment were evaluated for in vivo and in vitro inflammatory markers and endothelial cell function. METHODS Inflammatory markers (IL-6, matrix metalloproteinase-9 [MMP-9], vascular cell adhesion molecule-1 [VCAM-1], and von Willebrand factor [vWF]) from the incompetent great saphenous veins (GSVs) and from the systemic venous circulation were studied in 10 patients with CVD (C2s) before and after 2 months of sulodexide (2 × 500 lipasemic units/d) therapy. Serum obtained from the vein blood before and after sulodexide treatment was evaluated for in vitro cultured human umbilical vein endothelial cell function. RESULTS The serum collected from lower leg incompetent GSVs had significantly elevated levels of VCAM-1 (+29%, P < .001) compared with the serum from the systemic circulation. Endothelial cells exposed to the serum from the incompetent lower leg veins of the untreated CVD patients demonstrated higher stimulated synthesis of MMP-9 (+17%, P < .01), as well as increased markers of senescence (prolongation of population doubling time, β-galactosidase activity, and expression of p21 and p53 genes). CVD serum-induced senescent endothelial cells had a higher expression of genes regulating IL-6, MMP-9, VCAM-1, and vWF synthesis. The overall proinflammatory effect on endothelial cells by the serum collected from the incompetent GSVs was stronger as compared with the serum from the systemic circulation. Serum collected from the veins after sulodexide treatment caused lower levels of endothelial cell inflammatory markers as well as respective gene expression than serum obtained at the beginning of the study (before sulodexide treatment). Sulodexide application also reduced the inflammatory secretory activity of the senescent endothelial cells. Sulodexide treatment resulted in the decrease of the majority of the studied inflammatory parameters in both lower limb incompetent vein and systemic blood. CONCLUSIONS In patients with CVD, there are significant differences between circulating inflammatory markers analyzed from the lower leg incompetent GSV segments compared with the systemic circulation, indicating a higher inflammatory condition in CVD. Treatment with sulodexide reduces the proinflammatory and endothelial cell activation properties of the serum from patients with CVD. CLINICAL RELEVANCE The study documented the significant proinflammatory human vascular endothelial cell activation when exposed to the serum collected from the varicose veins as compared with the serum from the systemic circulation in patients with chronic venous disease (CVD). The inflammatory marker expression, endothelial dysfunction, and endothelial cell senescence transformation can be successfully controlled and downregulated by patients' exposure to the glycosaminoglycan (sulodexide) treatment. Further studies are needed to confirm if glycosaminoglycan application can prevent further CVD clinical progression due to potential CVD-related pathological processes' modulation and their downregulation.
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Affiliation(s)
- Adam Zieliński
- Section of Surgery, Vascular Surgery and Phlebology, doktorA Medical Center, Warsaw, Poland
| | | | - Andrzej Bręborowicz
- Department of Pathophysiology, Poznan University of Medical Sciences, Poznań, Poland; Department of Anatomy and Histology, University of Zielona Góra, Zielona Góra, Poland
| | - Katarzyna Kowalska
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poznań, Poland
| | - Maciej Zabel
- Department of Anatomy and Histology, University of Zielona Góra, Zielona Góra, Poland
| | - Teresa Wysocka
- Department of Anatomy and Histology, University of Zielona Góra, Zielona Góra, Poland
| | - Raouf A Khalil
- Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA
| | - Joseph D Raffetto
- VA Boston Healthcare System, Harvard Medical School, Brigham and Women's Hospital, Boston, MA
| | - Tomasz Urbanek
- Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Medical University of Silesia, Katowice, Poland.
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Sidnawi B, Zhou B, Chen Z, Sehgal C, Santhanam S, Wu Q. A comprehensive physics-based model for the brachial Artery's full flow mediated dilation (FMD) response observed during the FMD test. Comput Biol Med 2024; 179:108900. [PMID: 39029430 PMCID: PMC11324374 DOI: 10.1016/j.compbiomed.2024.108900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 07/01/2024] [Accepted: 07/14/2024] [Indexed: 07/21/2024]
Abstract
In this study, a physics-based model is developed to describe the entire flow mediated dilation (FMD) response. A parameter quantifying the arterial wall's tendency to recover arises from the model, thereby providing a more elaborate description of the artery's physical state, in concert with other parameters characterizing mechanotransduction and structural aspects of the arterial wall. The arterial diameter's behavior throughout the full response is successfully reproduced by the model. Experimental FMD response data were obtained from healthy volunteers. The model's parameters are then adjusted to yield the closest match to the observed experimental response, hence delivering the parameter values pertaining to each subject. This study establishes a foundation based on which future potential clinical applications can be introduced, where endothelial function and general cardiovascular health are inexpensively and noninvasively quantified.
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Affiliation(s)
- Bchara Sidnawi
- Department of Mechanical Engineering, Villanova University, PA, 19085, USA; Cellular Biomechanics and Sport Science Laboratory, Villanova University, PA, 19085, USA
| | - Bingjie Zhou
- Department of Mechanical Engineering, Villanova University, PA, 19085, USA; Cellular Biomechanics and Sport Science Laboratory, Villanova University, PA, 19085, USA
| | - Zhen Chen
- Department of Radiology, University of Pennsylvania, PA, 19104, USA
| | - Chandra Sehgal
- Department of Radiology, University of Pennsylvania, PA, 19104, USA
| | - Sridhar Santhanam
- Department of Mechanical Engineering, Villanova University, PA, 19085, USA
| | - Qianhong Wu
- Department of Mechanical Engineering, Villanova University, PA, 19085, USA; Cellular Biomechanics and Sport Science Laboratory, Villanova University, PA, 19085, USA.
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Han K, Ma S, Wang S, Qi X, Bian X, Li X. Interplay between endothelial glycocalyx layer and red blood cell in microvascular blood flow: A numerical study. Phys Rev E 2024; 110:034409. [PMID: 39425342 DOI: 10.1103/physreve.110.034409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 08/22/2024] [Indexed: 10/21/2024]
Abstract
The endothelial glycocalyx layer (EGL) plays a crucial role in regulating blood flow in microvessels. Experimental evidence suggests that there is greater blood flow resistance in vivo compared to in vitro, partially due to the presence of the EGL. However, the complex relationship between EGL deformation and blood cell behavior in shear flow and its quantification remains incompletely understood. To address this gap, we employ a particle-based numerical simulation technique to examine the interaction of the EGL with flowing red blood cells (RBCs) in microtubes. We examine changes in EGL deformation in response to variations in shear rate, EGL graft density, and contour height. Our results indicate that the alterations in EGL height are influenced by the mechanical properties of the EGL, flow conditions, and the RBC-EGL interaction. The flowing RBC compresses the EGL, causing a notable reduction in EGL height near the RBC flow. Additionally, we find that the presence of the EGL in the microtube results in increased RBC deformation and a wider gap between the RBC and tube wall due to spatial occupancy. The significant impact of the EGL on RBC flow is particularly evident in microtubes with diameters ranging from 7 to 10µm, a range consistent with notable differences in vascular flow resistance observed between in vivo and in vitro experiments. The simulation results shed insight on the dynamic interplay between RBC and the EGL in microvascular blood flow.
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Affiliation(s)
- Keqin Han
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Shuhao Ma
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Shuo Wang
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Xiaojing Qi
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Xin Bian
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
| | - Xuejin Li
- State Key Laboratory of Fluid Power and Mechatronic Systems, Department of Engineering Mechanics, and Center for X-Mechanics, Zhejiang University, Hangzhou 310027, China
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Balistreri CR, Di Giorgi L, Monastero R. Focus of endothelial glycocalyx dysfunction in ischemic stroke and Alzheimer's disease: Possible intervention strategies. Ageing Res Rev 2024; 99:102362. [PMID: 38830545 DOI: 10.1016/j.arr.2024.102362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/29/2024] [Accepted: 05/29/2024] [Indexed: 06/05/2024]
Abstract
The integrity of the endothelial glycocalyx (eGCX), a mixture of carbohydrates attached to proteins expressed on the surface of blood vessel endothelial cells (EC), is critical for the maintenance of homeostasis of the cardiovascular system and all systems of the human body, the endothelium being the critical component of the stroma of all tissues. Consequently, dysfunction of eGCX results in a dysfunctional cardiovascular wall and severe downstream cardiovascular events, which contribute to the onset of cardio- and cerebrovascular diseases and neurodegenerative disorders, as well as other age-related diseases (ARDs). The key role of eGCX dysfunction in the onset of ARDs is examined here, with a focus on the most prevalent neurological diseases: ischemic stroke and Alzheimer's disease. Furthermore, the advantages and limitations of some treatment strategies for anti-eGCX dysfunction are described, ranging from experimental drug therapies, which need to be better tested and explored not only in animal models but also in humans, as well as reprogramming, the use of nutraceuticals, which are emerging as regenerative and new approaches. The promotion of these strategies is essential to keep eGCX and endothelium healthy, as is the development of intravital (e.g., intravascular) tools to estimate eGCX health status and treatment efficacy, which could lead to advanced solutions to address ARDs.
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Affiliation(s)
- Carmela Rita Balistreri
- Cellular, Molecular and Clinical Pathological Laboratory, Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University of Palermo, Palermo 90134, Italy.
| | - Lucia Di Giorgi
- Memory and Parkinson's disease Center Policlinico "Paolo Giaccone", Palermo, and Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University of Palermo, Via La Loggia 1, Palermo 90129, Italy
| | - Roberto Monastero
- Memory and Parkinson's disease Center Policlinico "Paolo Giaccone", Palermo, and Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University of Palermo, Via La Loggia 1, Palermo 90129, Italy.
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14
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Akbarishandiz S, Khani S, Maia J. Adhesion dynamics of Janus nanocarriers to endothelial cells: A dissipative particle dynamics study. Phys Rev E 2024; 109:064408. [PMID: 39020963 DOI: 10.1103/physreve.109.064408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 03/28/2024] [Indexed: 07/20/2024]
Abstract
Janus nanocarriers (NCs) provide promising features in interfacial applications such as targeted drug delivery. Herein, we use dissipative particle dynamics simulations to study the adhesion dynamics of NCs with Janus ligand compositions to the endothelial cell as a function of a series of effects, such as the initial orientation, ligand density, shape, and size of Janus NCs. The Janus NCs, with its long axis parallel to the endothelial glycocalyx (EG) layer, has the best penetration depth due to its lower potential energy and the lowest shell entropy loss. Among different shapes of Janus NCs, both the potential energy and the EG entropy loss control the penetration. In fact, at the parallel orientations, Janus shapes with a robust mechanical strength and larger surface area at the EG/water interface can rotate and penetrate more efficiently. An increase in the ligand density of Janus NCs increases entropy losses of both the hydrophilic and the hydrophobic ligands and decreases the potential energy. Thus, for a specific Janus NCs, functionalizing with an appropriate ligand density would help driving forces prevail over barriers of penetration into the EG layer. For a particular ligand density, once the radius of the Janus NCs exceeds the appropriate size, barriers such as hydrophobic ligands and shell entropy losses are also reinforced significantly and surpass driving forces. Our observations reveal that entropy losses for hydrophobic ligands of Janus NCs and for the shell of NCs are decisive for the adhesion and penetration of Janus NCs to endothelial cells.
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15
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Zhang X, Leng S, Liu X, Hu X, Liu Y, Li X, Feng Q, Guo W, Li N, Sheng Z, Wang S, Peng J. Ion channel Piezo1 activation aggravates the endothelial dysfunction under a high glucose environment. Cardiovasc Diabetol 2024; 23:150. [PMID: 38702777 PMCID: PMC11067304 DOI: 10.1186/s12933-024-02238-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 04/16/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Vasculopathy is the most common complication of diabetes. Endothelial cells located in the innermost layer of blood vessels are constantly affected by blood flow or vascular components; thus, their mechanosensitivity plays an important role in mediating vascular regulation. Endothelial damage, one of the main causes of hyperglycemic vascular complications, has been extensively studied. However, the role of mechanosensitive signaling in hyperglycemic endothelial damage remains unclear. METHODS Vascular endothelial-specific Piezo1 knockout mice were generated to investigate the effects of Piezo1 on Streptozotocin-induced hyperglycemia and vascular endothelial injury. In vitro activation or knockdown of Piezo1 was performed to evaluate the effects on the proliferation, migration, and tubular function of human umbilical vein endothelial cells in high glucose. Reactive oxygen species production, mitochondrial membrane potential alternations, and oxidative stress-related products were used to assess the extent of oxidative stress damage caused by Piezo1 activation. RESULTS Our study found that in VECreERT2;Piezo1flox/flox mice with Piezo1 conditional knockout in vascular endothelial cells, Piezo1 deficiency alleviated streptozotocin-induced hyperglycemia with reduced apoptosis and abscission of thoracic aortic endothelial cells, and decreased the inflammatory response of aortic tissue caused by high glucose. Moreover, the knockout of Piezo1 showed a thinner thoracic aortic wall, reduced tunica media damage, and increased endothelial nitric oxide synthase expression in transgenic mice, indicating the relief of endothelial damage caused by hyperglycemia. We also showed that Piezo1 activation aggravated oxidative stress injury and resulted in severe dysfunction through the Ca2+-induced CaMKII-Nrf2 axis in human umbilical vein endothelial cells. In Piezo1 conditional knockout mice, Piezo1 deficiency partially restored superoxide dismutase activity and reduced malondialdehyde content in the thoracic aorta. Mechanistically, Piezo1 deficiency decreased CaMKII phosphorylation and restored the expression of Nrf2 and its downstream molecules HO-1 and NQO1. CONCLUSION In summary, our study revealed that Piezo1 is involved in high glucose-induced oxidative stress injury and aggravated endothelial dysfunction, which have great significance for alleviating endothelial damage caused by hyperglycemia.
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MESH Headings
- Animals
- Humans
- Human Umbilical Vein Endothelial Cells/metabolism
- Human Umbilical Vein Endothelial Cells/pathology
- Mice, Knockout
- Diabetes Mellitus, Experimental/metabolism
- Oxidative Stress
- Ion Channels/metabolism
- Ion Channels/genetics
- Blood Glucose/metabolism
- Nitric Oxide Synthase Type III/metabolism
- Mechanotransduction, Cellular
- NF-E2-Related Factor 2/metabolism
- NF-E2-Related Factor 2/genetics
- NF-E2-Related Factor 2/deficiency
- Cells, Cultured
- Cell Proliferation
- Apoptosis
- Male
- Diabetic Angiopathies/metabolism
- Diabetic Angiopathies/physiopathology
- Diabetic Angiopathies/pathology
- Diabetic Angiopathies/genetics
- Diabetic Angiopathies/etiology
- Cell Movement
- Mice, Inbred C57BL
- Reactive Oxygen Species/metabolism
- Aorta, Thoracic/metabolism
- Aorta, Thoracic/pathology
- Aorta, Thoracic/physiopathology
- Mice
- Streptozocin
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/physiopathology
- Endothelium, Vascular/pathology
- Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism
- Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics
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Affiliation(s)
- Xiaoyu Zhang
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Shaoqiu Leng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xinyue Liu
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiang Hu
- Advanced Medical Research Institute, Shandong University, Jinan, China
- Shandong Key Laboratory of Immunochematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yan Liu
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xin Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qi Feng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- National Key Laboratory for Innovation and Transformation of Luobing Theory; the Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Guo
- Institute of Hematology, the First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310029, China
| | - Nailin Li
- Department of Medicine-Solna, Cardiovascular Medicine Unit, Karolinska Institutet, Stockholm, Sweden
| | - Zi Sheng
- Shandong Key Laboratory of Immunochematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shuwen Wang
- Shandong Key Laboratory of Immunochematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
- National Key Laboratory for Innovation and Transformation of Luobing Theory; the Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Jun Peng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
- Advanced Medical Research Institute, Shandong University, Jinan, China.
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16
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Rabia B, Thanigaimani S, Golledge J. The potential involvement of glycocalyx disruption in abdominal aortic aneurysm pathogenesis. Cardiovasc Pathol 2024; 70:107629. [PMID: 38461960 DOI: 10.1016/j.carpath.2024.107629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 03/03/2024] [Accepted: 03/04/2024] [Indexed: 03/12/2024] Open
Abstract
BACKGROUND Abdominal aortic aneurysm is a weakening and expansion of the abdominal aorta. Currently, there is no drug treatment to limit abdominal aortic aneurysm growth. The glycocalyx is the outermost layer of the cell surface, mainly composed of glycosaminoglycans and proteoglycans. OBJECTIVE The aim of this review was to identify a potential relationship between glycocalyx disruption and abdominal aortic aneurysm pathogenesis. METHODS A narrative review of relevant published research was conducted. RESULTS Glycocalyx disruption has been reported to enhance vascular permeability, impair immune responses, dysregulate endothelial function, promote extracellular matrix remodeling and modulate mechanotransduction. All these effects are implicated in abdominal aortic aneurysm pathogenesis. Glycocalyx disruption promotes inflammation through exposure of adhesion molecules and release of proinflammatory mediators. Glycocalyx disruption affects how the endothelium responds to shear stress by reducing nitric oxide availabilty and adversely affecting the storage and release of several antioxidants, growth factors, and antithromotic proteins. These changes exacerbate oxidative stress, stimulate vascular smooth muscle cell dysfunction, and promote thrombosis, all effects implicated in abdominal aortic aneurysm pathogenesis. Deficiency of key component of the glycocalyx, such as syndecan-4, were reported to promote aneurysm formation and rupture in the angiotensin-II and calcium chloride induced mouse models of abdominal aortic aneurysm. CONCLUSION This review provides a summary of past research which suggests that glycocalyx disruption may play a role in abdominal aortic aneurysm pathogenesis. Further research is needed to establish a causal link between glycocalyx disruption and abdominal aortic aneurysm development.
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Affiliation(s)
- Bibi Rabia
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia; Department of Pharmacy, Hazara University, Mansehra 21300, Pakistan
| | - Shivshankar Thanigaimani
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia; The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland 4811, Australia
| | - Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia; The Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Queensland 4811, Australia; The Department of Vascular and Endovascular Surgery, The Townsville University Hospital, Townsville, Queensland 4810, Australia.
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17
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Ferreira G, Taylor A, Mensah SA. Deciphering the triad of endothelial glycocalyx, von Willebrand Factor, and P-selectin in inflammation-induced coagulation. Front Cell Dev Biol 2024; 12:1372355. [PMID: 38745860 PMCID: PMC11091309 DOI: 10.3389/fcell.2024.1372355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 04/11/2024] [Indexed: 05/16/2024] Open
Abstract
This review examines the endothelial glycocalyx's role in inflammation and explores its involvement in coagulation. The glycocalyx, composed of proteins and glycosaminoglycans, interacts with von Willebrand Factor and could play a crucial role in anchoring it to the endothelium. In inflammatory conditions, glycocalyx degradation may leave P-selectin as the only attachment point for von Willebrand Factor, potentially leading to uncontrolled release of ultralong von Willebrand Factor in the bulk flow in a shear stress-dependent manner. Identifying specific glycocalyx glycosaminoglycan interactions with von Willebrand Factor and P-selectin can offer insights into unexplored coagulation mechanisms.
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Affiliation(s)
- Guinevere Ferreira
- Biomedical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
- Mechanical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
| | - Alexandra Taylor
- Biomedical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
| | - Solomon A. Mensah
- Biomedical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
- Mechanical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
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18
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Farach-Carson MC, Wu D, França CM. Proteoglycans in Mechanobiology of Tissues and Organs: Normal Functions and Mechanopathology. PROTEOGLYCAN RESEARCH 2024; 2:e21. [PMID: 39584146 PMCID: PMC11584024 DOI: 10.1002/pgr2.21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/03/2024] [Indexed: 11/26/2024]
Abstract
Proteoglycans (PGs) are a diverse class of glycoconjugates that serve critical functions in normal mechanobiology and mechanopathology. Both the protein cores and attached glycosaminoglycan (GAG) chains function in mechanically-sensitive processes, and loss of either can contribute to development of pathological conditions. PGs function as key components of the extracellular matrix (ECM) where they can serve as mechanosensors in mechanosensitive tissues including bone, cartilage, tendon, blood vessels and soft organs. The mechanical properties of these tissues depend on the presence and function of PGs, which play important roles in tissue elasticity, osmolarity and pressure sensing, and response to physical activity. Tissue responses depend on cell surface mechanoreceptors that include integrins, CD44, voltage sensitive ion channels, transient receptor potential (TRP) and piezo channels. PGs contribute to cell and molecular interplay in wound healing, fibrosis, and cancer, where they transduce the mechanical properties of the ECM and influence the progression of various context-specific conditions and diseases. The PGs that are most important in mechanobiology vary depending on the tissue and its functions and functional needs. Perlecan, for example, is important in the mechanobiology of basement membranes, cardiac and skeletal muscle, while aggrecan plays a primary role in the mechanical properties of cartilage and joints. A variety of techniques have been used to study the mechanobiology of PGs, including atomic force microscopy, mouse knockout models, and in vitro cell culture experiments with 3D organoid models. These studies have helped to elucidate the tissue-specific roles that PGs play in cell-level mechanosensing and tissue mechanics. Overall, the study of PGs in mechanobiology is yielding fundamental new concepts in the molecular basis of mechanosensing that can open the door to the development of new treatments for a host of conditions related to mechanopathology.
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Affiliation(s)
- Mary C Farach-Carson
- Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054
- Departments of BioSciences and Bioengineering, Rice University, Houston, TX 77005
| | - Danielle Wu
- Department of Diagnostic and Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, TX 77054
- Departments of BioSciences and Bioengineering, Rice University, Houston, TX 77005
| | - Cristiane Miranda França
- Department of Oral Rehabilitation and Biosciences, School of Dentistry, Oregon Health & Science University, Portland, OR, 97201
- Knight Cancer Precision Biofabrication Hub, Cancer Early Detection Advanced Research Center (CEDAR), Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97201
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19
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Vittum Z, Cocchiaro S, Mensah SA. Basal endothelial glycocalyx's response to shear stress: a review of structure, function, and clinical implications. Front Cell Dev Biol 2024; 12:1371769. [PMID: 38562144 PMCID: PMC10982814 DOI: 10.3389/fcell.2024.1371769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 03/04/2024] [Indexed: 04/04/2024] Open
Abstract
The endothelial glycocalyx encompasses the entire endothelial cell, transducing extracellular signals and regulating vascular permeability and barrier functions. The apical glycocalyx, which forms the lumen of the vessel, and the basal glycocalyx, at the smooth muscle cell interface, are often investigated separately as they are exposed to vastly different stimuli. The apical glycocalyx directly senses fluid shear forces transmitting them intracellularly through connection to the cytoskeleton of the endothelial cell. The basal glycocalyx has demonstrated sensitivity to shear due to blood flow transmitted through the cytoskeleton, promoting alternate signaling processes. In this review, we discuss current literature on the basal glycocalyx's response to shear stress in the context of mechanotransduction and remodeling. The possible implications of basal glycocalyx degradation in pathologies are also explored. Finally, this review seeks to highlight how addressing the gaps discussed would improve our wholistic understanding of the endothelial glycocalyx and its role in maintaining vascular homeostasis.
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Affiliation(s)
- Zoe Vittum
- Biomedical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
| | - Samantha Cocchiaro
- Biomedical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
| | - Solomon A. Mensah
- Biomedical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
- Mechanical Engineering Department, Worcester Polytechnic Institute, Worcester, MA, United States
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20
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Chalkias A. Shear Stress and Endothelial Mechanotransduction in Trauma Patients with Hemorrhagic Shock: Hidden Coagulopathy Pathways and Novel Therapeutic Strategies. Int J Mol Sci 2023; 24:17522. [PMID: 38139351 PMCID: PMC10743945 DOI: 10.3390/ijms242417522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023] Open
Abstract
Massive trauma remains a leading cause of death and a global public health burden. Post-traumatic coagulopathy may be present even before the onset of resuscitation, and correlates with severity of trauma. Several mechanisms have been proposed to explain the development of abnormal coagulation processes, but the heterogeneity in injuries and patient profiles makes it difficult to define a dominant mechanism. Regardless of the pattern of death, a significant role in the pathophysiology and pathogenesis of coagulopathy may be attributed to the exposure of endothelial cells to abnormal physical forces and mechanical stimuli in their local environment. In these conditions, the cellular responses are translated into biochemical signals that induce/aggravate oxidative stress, inflammation, and coagulopathy. Microvascular shear stress-induced alterations could be treated or prevented by the development and use of innovative pharmacologic strategies that effectively target shear-mediated endothelial dysfunction, including shear-responsive drug delivery systems and novel antioxidants, and by targeting the venous side of the circulation to exploit the beneficial antithrombogenic profile of venous endothelial cells.
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Affiliation(s)
- Athanasios Chalkias
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-5158, USA;
- Outcomes Research Consortium, Cleveland, OH 44195, USA
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21
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Ishiko S, Ben Rahoma G, Kandhi S, Huang A, Sun D. Liposomal nanocarriers of preassembled glycocalyx expeditiously restore endothelial glycocalyx in endotoxemia. Am J Physiol Heart Circ Physiol 2023; 325:H645-H655. [PMID: 37505471 PMCID: PMC10643000 DOI: 10.1152/ajpheart.00196.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 07/26/2023] [Accepted: 07/26/2023] [Indexed: 07/29/2023]
Abstract
The endothelial glycocalyx (EG) is degraded early during sepsis, and currently available treatments are not effective in promptly restoring it. Here, we created liposomal nanocarriers of preassembled glycocalyx (LNPG) by synthesizing glycosylated syndecan-1 and inserting it into the lipid membrane of unilamellar liposomes. We hypothesized that LNPG would fuse with the endothelial cells where EG is degraded and restore EG in sepsis. We induced endotoxemia in C57BL/6J mice using lipopolysaccharides (LPS) and treated them with LNPG, saline, syndecan-1, or liposomes. LNPG significantly prolonged the survival time of LPS-treated mice compared with the other treatments. Immunostaining of en face mesenteric arteries of LPS-treated mice showed that syndecan-1 was fully restored after LNPG administration. In addition, EG height in microvasculature of mouse cremaster muscle was monitored using sidestream dark field imaging. LNPG restored the perfused boundary region (PBR), which is inversely related to EG dimensions, to the control level after LPS administration. Furthermore, flow-induced dilation in isolated mouse mesenteric arterioles was fully recovered after LNPG treatment in LPS-treated mice. In summary, our findings provide evidence of the therapeutic efficacy of LNPG in the LPS-induced mouse model of sepsis, achieved by expeditiously restoring EG through fusion of LNPG with the endothelial plasma membrane and recovery of endothelial function.NEW & NOTEWORTHY Vascular endothelial cells represent the first line of exposure to bacterial endotoxins. Here, we propose a novel therapeutic strategy using liposomes to deliver preassembled glycocalyx to vascular endothelial cell surface and consequently restore endothelial glycocalyx (EG). We tested liposomal nanocarriers of preassembled glycocalyx (LNPG) in vivo and ex vivo to establish for the first time their expeditious therapeutic efficacy in improving survival of lipopolysaccharides (LPS)-treated mice, as achieved by the restoration of EG and recovery of endothelial function.
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Affiliation(s)
- Shinya Ishiko
- Department of Medicine, New York Medical College, Valhalla, New York, United States
| | - Ghada Ben Rahoma
- Department of Physiology, New York Medical College, Valhalla, New York, United States
| | - Sharath Kandhi
- Department of Physiology, New York Medical College, Valhalla, New York, United States
| | - An Huang
- Department of Physiology, New York Medical College, Valhalla, New York, United States
| | - Dong Sun
- Department of Physiology, New York Medical College, Valhalla, New York, United States
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22
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Hayden MR. The Brain Endothelial Cell Glycocalyx Plays a Crucial Role in the Development of Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus. Life (Basel) 2023; 13:1955. [PMID: 37895337 PMCID: PMC10608474 DOI: 10.3390/life13101955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/07/2023] [Accepted: 09/22/2023] [Indexed: 10/29/2023] Open
Abstract
The brain endothelial cell (BEC) glycocalyx (ecGCx) is a BEC surface coating consisting of a complex interwoven polysaccharide (sweet husk) mesh-like network of membrane-bound proteoglycans, glycoproteins, and glycosaminoglycans (GAGs) covering the apical luminal layer of the brain endothelial cells. The ecGCx may be considered as the first barrier of a tripartite blood-brain barrier (BBB) consisting of (1) ecGCx; (2) BECs; and (3) an extravascular compartment of pericytes, the extracellular matrix, and perivascular astrocytes. Perturbations of this barrier allow for increased permeability in the postcapillary venule that will be permissive to both fluids, solutes, and proinflammatory peripherally derived leukocytes into the perivascular spaces (PVS) which result in enlargement as well as increased neuroinflammation. The ecGCx is known to have multiple functions, which include its physical and charge barrier, mechanical transduction, regulation of vascular permeability, modulation of inflammatory response, and anticoagulation functions. This review discusses each of the listed functions in detail and utilizes multiple transmission electron micrographs and illustrations to allow for a better understanding of the ecGCx structural and functional roles as it relates to enlarged perivascular spaces (EPVS). This is the fifth review of a quintet series that discuss the importance of EPVS from the perspective of the cells of brain barriers. Attenuation and/or loss of the ecGCx results in brain barrier disruption with increased permeability to proinflammatory leukocytes, fluids, and solutes, which accumulate in the postcapillary venule perivascular spaces. This accumulation results in obstruction and results in EPVS with impaired waste removal of the recently recognized glymphatic system. Importantly, EPVS are increasingly being regarded as a marker of cerebrovascular and neurodegenerative pathology.
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Affiliation(s)
- Melvin R Hayden
- Department of Internal Medicine, Endocrinology Diabetes and Metabolism, Diabetes and Cardiovascular Disease Center, University of Missouri School of Medicine, One Hospital Drive, Columbia, MO 65211, USA
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Marsh PL, Moore EE, Moore HB, Bunch CM, Aboukhaled M, Condon SM, Al-Fadhl MD, Thomas SJ, Larson JR, Bower CW, Miller CB, Pearson ML, Twilling CL, Reser DW, Kim GS, Troyer BM, Yeager D, Thomas SG, Srikureja DP, Patel SS, Añón SL, Thomas AV, Miller JB, Van Ryn DE, Pamulapati SV, Zimmerman D, Wells B, Martin PL, Seder CW, Aversa JG, Greene RB, March RJ, Kwaan HC, Fulkerson DH, Vande Lune SA, Mollnes TE, Nielsen EW, Storm BS, Walsh MM. Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies. Front Immunol 2023; 14:1230049. [PMID: 37795086 PMCID: PMC10546929 DOI: 10.3389/fimmu.2023.1230049] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 07/12/2023] [Indexed: 10/06/2023] Open
Abstract
Iatrogenic vascular air embolism is a relatively infrequent event but is associated with significant morbidity and mortality. These emboli can arise in many clinical settings such as neurosurgery, cardiac surgery, and liver transplantation, but more recently, endoscopy, hemodialysis, thoracentesis, tissue biopsy, angiography, and central and peripheral venous access and removal have overtaken surgery and trauma as significant causes of vascular air embolism. The true incidence may be greater since many of these air emboli are asymptomatic and frequently go undiagnosed or unreported. Due to the rarity of vascular air embolism and because of the many manifestations, diagnoses can be difficult and require immediate therapeutic intervention. An iatrogenic air embolism can result in both venous and arterial emboli whose anatomic locations dictate the clinical course. Most clinically significant iatrogenic air emboli are caused by arterial obstruction of small vessels because the pulmonary gas exchange filters the more frequent, smaller volume bubbles that gain access to the venous circulation. However, there is a subset of patients with venous air emboli caused by larger volumes of air who present with more protean manifestations. There have been significant gains in the understanding of the interactions of fluid dynamics, hemostasis, and inflammation caused by air emboli due to in vitro and in vivo studies on flow dynamics of bubbles in small vessels. Intensive research regarding the thromboinflammatory changes at the level of the endothelium has been described recently. The obstruction of vessels by air emboli causes immediate pathoanatomic and immunologic and thromboinflammatory responses at the level of the endothelium. In this review, we describe those immunologic and thromboinflammatory responses at the level of the endothelium as well as evaluate traditional and novel forms of therapy for this rare and often unrecognized clinical condition.
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Affiliation(s)
- Phillip L. Marsh
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
| | - Ernest E. Moore
- Department of Surgery, Ernest E. Moore Shock Trauma Center at Denver Health and University of Colorado Health Sciences Center, Denver, CO, United States
| | - Hunter B. Moore
- University of Colorado Health Transplant Surgery - Anschutz Medical Campus, Aurora, CO, United States
| | - Connor M. Bunch
- Department of Emergency Medicine, Henry Ford Hospital, Detroit, MI, United States
| | - Michael Aboukhaled
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
| | - Shaun M. Condon
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
- Department of Emergency Medicine, Henry Ford Hospital, Detroit, MI, United States
| | | | - Samuel J. Thomas
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
| | - John R. Larson
- Department of Emergency Medicine, Goshen Health, Goshen, IN, United States
| | - Charles W. Bower
- Department of Emergency Medicine, Goshen Health, Goshen, IN, United States
| | - Craig B. Miller
- Department of Family Medicine, Saint Joseph Health System, Mishawaka, IN, United States
| | - Michelle L. Pearson
- Department of Family Medicine, Saint Joseph Health System, Mishawaka, IN, United States
| | | | - David W. Reser
- Department of Emergency Medicine, Goshen Health, Goshen, IN, United States
| | - George S. Kim
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
- Department of Emergency Medicine, Goshen Health, Goshen, IN, United States
| | - Brittany M. Troyer
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
- Department of Emergency Medicine, Goshen Health, Goshen, IN, United States
| | - Doyle Yeager
- Department of Emergency Medicine, Goshen Health, Goshen, IN, United States
| | - Scott G. Thomas
- Department of Trauma & Surgical Research Services, South Bend, IN, United States
| | - Daniel P. Srikureja
- Department of Trauma & Surgical Research Services, South Bend, IN, United States
| | - Shivani S. Patel
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
- Department of Emergency Medicine, Henry Ford Hospital, Detroit, MI, United States
| | - Sofía L. Añón
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
| | - Anthony V. Thomas
- Indiana University School of Medicine, South Bend, IN, United States
| | - Joseph B. Miller
- Department of Emergency Medicine, Henry Ford Hospital, Detroit, MI, United States
| | - David E. Van Ryn
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
- Department of Emergency Medicine, Goshen Health, Goshen, IN, United States
- Department of Emergency Medicine, Beacon Health System, Elkhart, IN, United States
| | - Saagar V. Pamulapati
- Department of Internal Medicine, Mercy Health Internal Medicine Residency Program, Rockford, IL, United States
| | - Devin Zimmerman
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
| | - Byars Wells
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
| | - Peter L. Martin
- Department of Emergency Medicine, Goshen Health, Goshen, IN, United States
| | - Christopher W. Seder
- Department of Cardiovascular and Thoracic Surgery, RUSH Medical College, Chicago, IL, United States
| | - John G. Aversa
- Department of Cardiovascular and Thoracic Surgery, RUSH Medical College, Chicago, IL, United States
| | - Ryan B. Greene
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
| | - Robert J. March
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
| | - Hau C. Kwaan
- Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, IL, United States
| | - Daniel H. Fulkerson
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
- Department of Trauma & Surgical Research Services, South Bend, IN, United States
| | - Stefani A. Vande Lune
- Department of Emergency Medicine, Naval Medical Center Portsmouth, Portsmouth, VA, United States
| | - Tom E. Mollnes
- Research Laboratory, Nordland Hospital, Bodø, Norway
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Immunology, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Erik W. Nielsen
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Anesthesia and Intensive Care Medicine, Surgical Clinic, Nordland Hospital, Bodø, Norway
- Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway
- Faculty of Nursing and Health Sciences, Nord University, Bodø, Norway
| | - Benjamin S. Storm
- Department of Anesthesia and Intensive Care Medicine, Surgical Clinic, Nordland Hospital, Bodø, Norway
- Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway
- Faculty of Nursing and Health Sciences, Nord University, Bodø, Norway
| | - Mark M. Walsh
- Department of Emergency Medicine, Saint Joseph Regional Medical Center, Mishawaka, IN, United States
- Indiana University School of Medicine, South Bend, IN, United States
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24
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Anand T, Reyes AA, Sjoquist MC, Magnotti L, Joseph B. Resuscitating the Endothelial Glycocalyx in Trauma and Hemorrhagic Shock. ANNALS OF SURGERY OPEN 2023; 4:e298. [PMID: 37746602 PMCID: PMC10513357 DOI: 10.1097/as9.0000000000000298] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 05/20/2023] [Indexed: 09/26/2023] Open
Abstract
The endothelium is lined by a protective mesh of proteins and carbohydrates called the endothelial glycocalyx (EG). This layer creates a negatively charged gel-like barrier between the vascular environment and the surface of the endothelial cell. When intact the EG serves multiple functions, including mechanotransduction, cell signaling, regulation of permeability and fluid exchange across the microvasculature, and management of cell-cell interactions. In trauma and/or hemorrhagic shock, the glycocalyx is broken down, resulting in the shedding of its individual components. The shedding of the EG is associated with increased systemic inflammation, microvascular permeability, and flow-induced vasodilation, leading to further physiologic derangements. Animal and human studies have shown that the greater the severity of the injury, the greater the degree of shedding, which is associated with poor patient outcomes. Additional studies have shown that prioritizing certain resuscitation fluids, such as plasma, cryoprecipitate, and whole blood over crystalloid shows improved outcomes in hemorrhaging patients, potentially through a decrease in EG shedding impacting downstream signaling. The purpose of the following paragraphs is to briefly describe the EG, review the impact of EG shedding and hemorrhagic shock, and begin entertaining the notion of directed resuscitation. Directed resuscitation emphasizes transitioning from macroscopic 1:1 resuscitation to efforts that focus on minimizing EG shedding and maximizing its reconstitution.
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Affiliation(s)
- Tanya Anand
- From the Department of Surgery, Division of Trauma, Critical Care, Burns, and Emergency Surgery, The University of Arizona, Tucson, AZ
| | | | - Michael C. Sjoquist
- Department of Surgery, University of Arizona College of Medicine, Tucson, AZ
| | - Louis Magnotti
- From the Department of Surgery, Division of Trauma, Critical Care, Burns, and Emergency Surgery, The University of Arizona, Tucson, AZ
| | - Bellal Joseph
- From the Department of Surgery, Division of Trauma, Critical Care, Burns, and Emergency Surgery, The University of Arizona, Tucson, AZ
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25
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Aitken C, Mehta V, Schwartz MA, Tzima E. Mechanisms of endothelial flow sensing. NATURE CARDIOVASCULAR RESEARCH 2023; 2:517-529. [PMID: 39195881 DOI: 10.1038/s44161-023-00276-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 04/14/2023] [Indexed: 08/29/2024]
Abstract
Fluid shear stress plays a key role in sculpting blood vessels during development, in adult vascular homeostasis and in vascular pathologies. During evolution, endothelial cells evolved several mechanosensors that convert physical forces into biochemical signals, a process termed mechanotransduction. This Review discusses our understanding of endothelial flow sensing and suggests important questions for future investigation.
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Affiliation(s)
- Claire Aitken
- Wellcome Centre for Human Genetics, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Vedanta Mehta
- Wellcome Centre for Human Genetics, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Martin A Schwartz
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, and Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT, USA.
| | - Ellie Tzima
- Wellcome Centre for Human Genetics, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
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26
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Li Y, Sun Z, Zhu H, Sun Y, Shteyman DB, Markx S, Leong KW, Xu B, Fu BM. Inhibition of Abl Kinase by Imatinib Can Rescue the Compromised Barrier Function of 22q11.2DS Patient-iPSC-Derived Blood-Brain Barriers. Cells 2023; 12:422. [PMID: 36766762 PMCID: PMC9913366 DOI: 10.3390/cells12030422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/06/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
We have previously established that the integrity of the induced blood-brain barrier (iBBB) formed by brain microvascular endothelial cells derived from the iPSC of 22q11.2 DS (22q11.2 Deletion Syndrome, also called DiGeorge Syndrome) patients is compromised. We tested the possibility that the haploinsufficiency of CRKL, a gene within the 22q11.2 DS deletion region, contributes to the deficit. The CRKL is a major substrate of the Abl tyrosine kinase, and the Abl/CRKL signaling pathway is critical for endothelial barrier functions. Imatinib, an FDA-approved drug, inhibits Abl kinase and has been used to treat various disorders involving vascular leakages. To test if imatinib can restore the compromised iBBB, we treated the patient's iBBB with imatinib. After treatment, both trans-endothelial electrical resistance and solute permeability returned to comparable levels of the control iBBB. Correspondingly, changes in tight junctions and endothelial glycocalyx of the iBBB were also restored. Western blotting showed that imatinib increased the level of active forms of the CRKL protein. A transcriptome study revealed that imatinib up-regulated genes in the signaling pathways responsible for the protein modification process and down-regulated those for cell cycling. The KEGG pathway analysis further suggested that imatinib improved the gene expression of the CRKL signaling pathway and tight junctions, which agrees with our expectations and the observations at protein levels. Our results indicate that the 22q11.2DS iBBB is at least partially caused by the haploinsufficiency of CRKL, which can be rescued by imatinib via its effects on the Abl/CRKL signaling pathway. Our findings uncover a novel disease mechanism associated with 22q11.2DS.
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Affiliation(s)
- Yunfei Li
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA
| | - Zhixiong Sun
- Department of Psychiatry, Columbia University, New York, NY 10032, USA
| | - Huixiang Zhu
- Department of Psychiatry, Columbia University, New York, NY 10032, USA
| | - Yan Sun
- Department of Psychiatry, Columbia University, New York, NY 10032, USA
| | - David B. Shteyman
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA
| | - Sander Markx
- Department of Psychiatry, Columbia University, New York, NY 10032, USA
| | - Kam W. Leong
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Bin Xu
- Department of Psychiatry, Columbia University, New York, NY 10032, USA
| | - Bingmei M. Fu
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA
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A stabilized CXCL9(74-103)-derived peptide selectively inhibits proliferation, adhesion and metastasis of tumor cells that express high levels of heparan sulfate. Int J Biol Macromol 2022; 222:2808-2822. [PMID: 36272565 DOI: 10.1016/j.ijbiomac.2022.10.060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/06/2022] [Accepted: 10/07/2022] [Indexed: 11/05/2022]
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28
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Decay-Accelerating Factor Creates an Organ-Protective Phenotype after Hemorrhage in Conscious Rats. Int J Mol Sci 2022; 23:ijms232113563. [PMID: 36362350 PMCID: PMC9655774 DOI: 10.3390/ijms232113563] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/29/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
Preclinical and clinical studies have shown that traumatic hemorrhage (TH) induces early complement cascade activation, leading to inflammation-associated multiple-organ dysfunction syndrome (MODS). Several previous studies have demonstrated the beneficial effects of complement inhibition in anesthetized (unconscious) animal models of hemorrhage. Anesthetic agents profoundly affect the immune response, microcirculation response, and coagulation patterns and thereby may confound the TH research data acquired. However, no studies have addressed the effect of complement inhibition on inflammation-driven MODS in a conscious model of hemorrhage. This study investigated whether early administration of decay-accelerating factor (CD55/DAF, a complement C3/C5 inhibitor) alleviates hemorrhage-induced organ damage and how DAF modulates hemorrhage-induced organ damage. DAF was administered to unanesthetized male Sprague Dawley rats subjected to pressure-controlled hemorrhage followed by a prolonged (4 h) hypotensive resuscitation with or without lactated Ringer’s (LR). We assessed DAF effects on organ protection, tissue levels of complement synthesis and activation, T lymphocyte infiltration, fluid resuscitation requirements, and metabolic acidosis. Hemorrhage with (HR) or without (H) LR resuscitation resulted in significantly increased C3, C5a, and C5b-9 deposition in the lung and intestinal tissues. HR rats had significantly higher tissue levels of complement activation/deposition (particularly C5a and C5b-9 in the lung tissues), a higher but not significant amount of C3 and C5b-9 pulmonary microvascular deposition, and relatively severe injury in the lung and intestinal tissues compared to H rats. DAF treatment significantly reduced tissue C5b-9 formation and C3 deposition in the H or HR rats and decreased tissue levels of C5a and C3 mRNA in the HR rats. This treatment prevented the injury of these organs, improved metabolic acidosis, reduced fluid resuscitation requirements, and decreased T-cell infiltration in lung tissues. These findings suggest that DAF has the potential as an organ-protective adjuvant treatment for TH during prolonged damage control resuscitation.
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Yang Z, Le TD, Simovic MO, Liu B, Fraker TL, Cancio TS, Cap AP, Wade CE, DalleLucca JJ, Li Y. Traumatized triad of complementopathy, endotheliopathy, and coagulopathy ˗ Impact on clinical outcomes in severe polytrauma patients. Front Immunol 2022; 13:991048. [PMID: 36341368 PMCID: PMC9632416 DOI: 10.3389/fimmu.2022.991048] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 10/07/2022] [Indexed: 11/13/2022] Open
Abstract
Complementopathy, endotheliopathy, and coagulopathy following a traumatic injury are key pathophysiological mechanisms potentially associated with multiple-organ failure (MOF) and mortality. However, the heterogeneity in the responses of complementopathy, endotheliopathy, and coagulopathy to trauma, the nature and extent of their interplay, and their relationship to clinical outcomes remain unclear. Fifty-four poly-trauma patients were enrolled and divided into three subgroups based on their ISS. Biomarkers in blood plasma reflecting complement activation, endothelial damage, and coagulopathy were measured starting from admission to the emergency department and at 3, 6, 12, 24, and 120 hours after admission. Comparative analyses showed that severely injured patients (ISS>24) were associated with longer days on mechanical ventilation, in the intensive care unit and hospital stays, and a higher incidence of hyperglycemia, bacteremia, respiratory failure and pneumonia compared to mildly (ISS<16) or moderately (ISS=16-24) injured patients. In this trauma cohort, complement was activated early, primarily through the alternative complement pathway. As measured in blood plasma, severely injured patients had significantly higher levels of complement activation products (C3a, C5a, C5b-9, and Bb), endothelial damage markers (syndecan-1, sTM, sVEGFr1, and hcDNA), and fibrinolytic markers (D-dimer and LY30) compared to less severely injured patients. Severely injured patients also had significantly lower thrombin generation (ETP and peak) and lower levels of coagulation factors (I, V, VIII, IX, protein C) than less severely injured patients. Complement activation correlated with endothelial damage and hypocoagulopathy. Logistic regression analyses revealed that Bb >1.57 μg/ml, syndecan-1 >66.6 ng/ml or D-dimer >6 mg/L at admission were associated with a higher risk of MOF/mortality. After adjusting for ISS, each increase of the triadic score defined above (Bb>1.57 µg/ml/Syndecan-1>66.6 ng/ml/D-dimer>6.0mg/L) was associated with a 6-fold higher in the odds ratio of MOF/death [OR: 6.83 (1.04-44.96, P=0.046], and a 4-fold greater in the odds of infectious complications [OR: 4.12 (1.04-16.36), P=0.044]. These findings provide preliminary evidence of two human injury response endotypes (traumatized triad and non-traumatized triad) that align with clinical trajectory, suggesting a potential endotype defined by a high triadic score. Patients with this endotype may be considered for timely intervention to create a pro-survival/organ-protective phenotype and improve clinical outcomes.
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Affiliation(s)
- Zhangsheng Yang
- United States Army Institute of Surgical Research, Joint Base San Antonio Fort Sam Houston, TX, United States
| | - Tuan D. Le
- United States Army Institute of Surgical Research, Joint Base San Antonio Fort Sam Houston, TX, United States
| | - Milomir O. Simovic
- United States Army Institute of Surgical Research, Joint Base San Antonio Fort Sam Houston, TX, United States
- Trauma Immunomodulation Program, The Geneva Foundation, Tacoma, WA, United States
| | - Bin Liu
- United States Army Institute of Surgical Research, Joint Base San Antonio Fort Sam Houston, TX, United States
| | - Tamara L. Fraker
- United States Army Institute of Surgical Research, Joint Base San Antonio Fort Sam Houston, TX, United States
- Trauma Immunomodulation Program, The Geneva Foundation, Tacoma, WA, United States
| | - Tomas S. Cancio
- United States Army Institute of Surgical Research, Joint Base San Antonio Fort Sam Houston, TX, United States
| | - Andrew P. Cap
- United States Army Institute of Surgical Research, Joint Base San Antonio Fort Sam Houston, TX, United States
| | - Charles E. Wade
- Department of Surgery, University of Texas Health McGovern Medical School, Houston, TX, United States
| | - Jurandir J. DalleLucca
- Scientific Research Department, Armed Forces Radiobiological Research Institute, Bethesda, MD, United States
| | - Yansong Li
- United States Army Institute of Surgical Research, Joint Base San Antonio Fort Sam Houston, TX, United States
- Trauma Immunomodulation Program, The Geneva Foundation, Tacoma, WA, United States
- *Correspondence: Yansong Li,
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30
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Renaldo AC, Lane MR, Shapiro SR, Mobin F, Jordan JE, Williams TK, Neff LP, Gayzik FS, Rahbar E. Development of a computational fluid dynamic model to investigate the hemodynamic impact of REBOA. Front Physiol 2022; 13:1005073. [PMID: 36311232 PMCID: PMC9606623 DOI: 10.3389/fphys.2022.1005073] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/16/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a lifesaving intervention for major truncal hemorrhage. Balloon-tipped arterial catheters are inserted via the femoral artery to create a temporary occlusion of the aorta, which minimizes the rate of internal bleeding until definitive surgery can be conducted. There is growing concern over the resultant hypoperfusion and potential damage to tissues and organs downstream of REBOA. To better understand the acute hemodynamic changes imposed by REBOA, we developed a three-dimensional computational fluid dynamic (CFD) model under normal, hemorrhage, and aortic occlusion conditions. The goal was to characterize the acute hemodynamic changes and identify regions within the aortic vascular tree susceptible to abnormal flow and shear stress. Methods: Hemodynamic data from established porcine hemorrhage models were used to build a CFD model. Swine underwent 20% controlled hemorrhage and were randomized to receive a full or partial aortic occlusion. Using CT scans, we generated a pig-specific aortic geometry and imposed physiologically relevant inlet flow and outlet pressure boundary conditions to match in vivo data. By assuming non-Newtonian fluid properties, pressure, velocity, and shear stresses were quantified over a cardiac cycle. Results: We observed a significant rise in blood pressure (∼147 mmHg) proximal to REBOA, which resulted in increased flow and shear stress within the ascending aorta. Specifically, we observed high levels of shear stress within the subclavian arteries (22.75 Pa). Alternatively, at the site of full REBOA, wall shear stress was low (0.04 ± 9.07E-4 Pa), but flow oscillations were high (oscillatory shear index of 0.31). Comparatively, partial REBOA elevated shear levels to 84.14 ± 19.50 Pa and reduced flow oscillations. Our numerical simulations were congruent within 5% of averaged porcine experimental data over a cardiac cycle. Conclusion: This CFD model is the first to our knowledge to quantify the acute hemodynamic changes imposed by REBOA. We identified areas of low shear stress near the site of occlusion and high shear stress in the subclavian arteries. Future studies are needed to determine the optimal design parameters of endovascular hemorrhage control devices that can minimize flow perturbations and areas of high shear.
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Affiliation(s)
- Antonio C. Renaldo
- Department of Biomedical Engineering, Wake Forest School of Medicine, Winston Salem, NC, United States
- Virginia Tech—Wake Forest University School of Biomedical Engineering and Sciences, Blacksburg, VA, United States
| | - Magan R. Lane
- Department of Vascular and Endovascular Surgery, Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Sophie R. Shapiro
- Department of Biomedical Engineering, Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Fahim Mobin
- Department of Biomedical Engineering, Wake Forest School of Medicine, Winston Salem, NC, United States
- Virginia Tech—Wake Forest University School of Biomedical Engineering and Sciences, Blacksburg, VA, United States
| | - James E. Jordan
- Department of Cardiothoracic Surgery, Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Timothy K. Williams
- Department of Vascular and Endovascular Surgery, Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Lucas P. Neff
- Department of General Surgery, Section of Pediatric Surgery, Wake Forest School of Medicine, Winston Salem, NC, United States
| | - F. Scott Gayzik
- Department of Biomedical Engineering, Wake Forest School of Medicine, Winston Salem, NC, United States
- Virginia Tech—Wake Forest University School of Biomedical Engineering and Sciences, Blacksburg, VA, United States
- Center for Injury Biomechanics, Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Elaheh Rahbar
- Department of Biomedical Engineering, Wake Forest School of Medicine, Winston Salem, NC, United States
- Virginia Tech—Wake Forest University School of Biomedical Engineering and Sciences, Blacksburg, VA, United States
- Center for Injury Biomechanics, Wake Forest School of Medicine, Winston Salem, NC, United States
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31
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Dobson GP, Morris JL, Letson HL. Why are bleeding trauma patients still dying? Towards a systems hypothesis of trauma. Front Physiol 2022; 13:990903. [PMID: 36148305 PMCID: PMC9485567 DOI: 10.3389/fphys.2022.990903] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 08/12/2022] [Indexed: 12/14/2022] Open
Abstract
Over the years, many explanations have been put forward to explain early and late deaths following hemorrhagic trauma. Most include single-event, sequential contributions from sympathetic hyperactivity, endotheliopathy, trauma-induced coagulopathy (TIC), hyperinflammation, immune dysfunction, ATP deficit and multiple organ failure (MOF). We view early and late deaths as a systems failure, not as a series of manifestations that occur over time. The traditional approach appears to be a by-product of last century's highly reductionist, single-nodal thinking, which also extends to patient management, drug treatment and drug design. Current practices appear to focus more on alleviating symptoms rather than addressing the underlying problem. In this review, we discuss the importance of the system, and focus on the brain's "privilege" status to control secondary injury processes. Loss of status from blood brain barrier damage may be responsible for poor outcomes. We present a unified Systems Hypothesis Of Trauma (SHOT) which involves: 1) CNS-cardiovascular coupling, 2) Endothelial-glycocalyx health, and 3) Mitochondrial integrity. If central control of cardiovascular coupling is maintained, we hypothesize that the endothelium will be protected, mitochondrial energetics will be maintained, and immune dysregulation, inflammation, TIC and MOF will be minimized. Another overlooked contributor to early and late deaths following hemorrhagic trauma is from the trauma of emergent surgery itself. This adds further stress to central control of secondary injury processes. New point-of-care drug therapies are required to switch the body's genomic and proteomic programs from an injury phenotype to a survival phenotype. Currently, no drug therapy exists that targets the whole system following major trauma.
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Affiliation(s)
- Geoffrey P. Dobson
- Heart and Trauma Research Laboratory, College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia
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Dobson GP, Morris JL, Letson HL. Immune dysfunction following severe trauma: A systems failure from the central nervous system to mitochondria. Front Med (Lausanne) 2022; 9:968453. [PMID: 36111108 PMCID: PMC9468749 DOI: 10.3389/fmed.2022.968453] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/01/2022] [Indexed: 12/20/2022] Open
Abstract
When a traumatic injury exceeds the body's internal tolerances, the innate immune and inflammatory systems are rapidly activated, and if not contained early, increase morbidity and mortality. Early deaths after hospital admission are mostly from central nervous system (CNS) trauma, hemorrhage and circulatory collapse (30%), and later deaths from hyperinflammation, immunosuppression, infection, sepsis, acute respiratory distress, and multiple organ failure (20%). The molecular drivers of secondary injury include damage associated molecular patterns (DAMPs), pathogen associated molecular patterns (PAMPs) and other immune-modifying agents that activate the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic stress response. Despite a number of drugs targeting specific anti-inflammatory and immune pathways showing promise in animal models, the majority have failed to translate. Reasons for failure include difficulty to replicate the heterogeneity of humans, poorly designed trials, inappropriate use of specific pathogen-free (SPF) animals, ignoring sex-specific differences, and the flawed practice of single-nodal targeting. Systems interconnectedness is a major overlooked factor. We argue that if the CNS is protected early after major trauma and control of cardiovascular function is maintained, the endothelial-glycocalyx will be protected, sufficient oxygen will be delivered, mitochondrial energetics will be maintained, inflammation will be resolved and immune dysfunction will be minimized. The current challenge is to develop new systems-based drugs that target the CNS coupling of whole-body function.
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Affiliation(s)
- Geoffrey P. Dobson
- Heart and Trauma Research Laboratory, College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia
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33
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Haymet AB, Pinto N, Peden S, Cohen T, Vallely MP, McGiffin D, Naidoo R, Jenkins J, Suen JY, Fraser JF. Current intraoperative storage and handling practices of autologous bypass conduit: A survey of the royal australasian college of surgeons. Front Surg 2022; 9:956177. [PMID: 36090334 PMCID: PMC9458927 DOI: 10.3389/fsurg.2022.956177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/09/2022] [Indexed: 11/28/2022] Open
Abstract
During bypass surgery for peripheral arterial occlusive disease and ischaemic heart disease, autologous graft conduit including great saphenous veins and radial arteries are frequently stored in solution. Endothelial damage adversely affects the performance and patency of autologous bypass grafts, and intraoperative graft storage solutions have been shown to influence this process. The distribution of storage solutions currently used amongst Cardiothoracic and Vascular Surgeons from Australia and New Zealand is not well defined in the literature. The aim of this study was to determine current practices regarding autologous graft storage and handling amongst this cohort of surgeons, and discuss their potential relevance in the context of early graft failure. From this survey, the most frequently used storage solutions were heparinized saline for great saphenous veins, and pH-buffered solutions for radial arteries. Duration of storage was 30–45 min for almost half of respondents, although responses to this question were limited. Further research is required to investigate whether ischaemic endothelial injury generates a prothrombotic state, whether different storage media can alter this state, and whether this is directly associated with clinical outcomes of interest such as early graft failure.
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Affiliation(s)
- AB Haymet
- Department of Vascular Surgery, The Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
- Critical Care Research Group, The Prince Charles Hospital, Chermside, QLD, Australia
- Faculty of Medicine, University of Queensland, St Lucia, QLD, Australia
- Correspondence: Andrew B Haymet
| | - N Pinto
- Department of Vascular Surgery, The Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
- Herston Biofabrication Institute, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
| | - S Peden
- Department of Vascular Surgery, The Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
| | - T Cohen
- Department of Vascular Surgery, The Princess Alexandra Hospital, Woolloongabba, QLD, Australia
| | - MP Vallely
- Department of Cardiovascular Surgery, Mount Sinai Morningside/Icahn School of Medicine, New York, NY, United States
| | - D McGiffin
- Department of Cardiothoracic Surgery, The Alfred Hospital, Melbourne, VIC, Australia
- Faculty of Medicine, Monash University, Melbourne, Australia
| | - R Naidoo
- Department of Cardiothoracic Surgery, The Prince Charles Hospital, Chermside, QLD, Australia
| | - J Jenkins
- Department of Vascular Surgery, The Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
- Herston Biofabrication Institute, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
| | - JY Suen
- Critical Care Research Group, The Prince Charles Hospital, Chermside, QLD, Australia
- Faculty of Medicine, University of Queensland, St Lucia, QLD, Australia
| | - JF Fraser
- Critical Care Research Group, The Prince Charles Hospital, Chermside, QLD, Australia
- Faculty of Medicine, University of Queensland, St Lucia, QLD, Australia
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Mutengo KH, Masenga SK, Mwesigwa N, Patel KP, Kirabo A. Hypertension and human immunodeficiency virus: A paradigm for epithelial sodium channels? Front Cardiovasc Med 2022; 9:968184. [PMID: 36093171 PMCID: PMC9452753 DOI: 10.3389/fcvm.2022.968184] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/10/2022] [Indexed: 02/03/2023] Open
Abstract
Hypertension is a risk factor for end organ damage and death and is more common in persons with HIV compared to the general population. Several mechanisms have been studied in the pathogenesis of hypertension. Current evidence suggests that the epithelial sodium channel (ENaC) plays a key role in regulating blood pressure through the transport of sodium and water across membranes in the kidney tubules, resulting in retention of sodium and water and an altered fluid balance. However, there is scarcity of information that elucidates the role of ENaC in HIV as it relates to increasing the risk for development or pathogenesis of hypertension. This review summarized the evidence to date implicating a potential role for altered ENaC activity in contributing to hypertension in patients with HIV.
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Affiliation(s)
- Katongo H. Mutengo
- School of Medicine and Health Sciences, HAND Research Group, Mulungushi University, Livingstone Campus, Livingstone, Zambia,School of Public Health and Medicine, University of Zambia, Lusaka, Zambia
| | - Sepiso K. Masenga
- School of Medicine and Health Sciences, HAND Research Group, Mulungushi University, Livingstone Campus, Livingstone, Zambia,School of Public Health and Medicine, University of Zambia, Lusaka, Zambia
| | - Naome Mwesigwa
- Department of Medicine and Dentistry, Kampala International University, Kampala, Uganda
| | - Kaushik P. Patel
- Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Annet Kirabo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States,*Correspondence: Annet Kirabo,
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Sidnawi B, Santhanam S, Sehgal C, Wu Q. On the examination of the viscous response of the brachial artery during flow-mediated dilation. J Mech Behav Biomed Mater 2022; 131:105255. [PMID: 35500495 PMCID: PMC11141792 DOI: 10.1016/j.jmbbm.2022.105255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 04/04/2022] [Accepted: 04/22/2022] [Indexed: 10/18/2022]
Abstract
In this study, mechanotransduction is investigated through a physics-based viscoelastic model describing the arterial diameter response during a brachial artery flow mediated dilation (BAFMD) test. The study is a significant extension of two earlier studies by the same group, where only the elastic response was considered. Experimental BAFMD responses were collected from 12 healthy volunteers. The arterial wall's elastic and viscous properties were treated as local variable quantities depending on the wall shear stress (WSS) sensed by mechanotransduction. The dimensionless parameters, arising from the model which serve as a quantitative assessment of the artery's physical state, were adjusted to replicate the experimental response. Among those dimensionless parameters, the viscoelastic ratio, which reflects the relative strength of the viscous response compared to its elastic counterpart, is of special relevance to this paper's main conclusion. Based on the results, it is concluded that the arterial wall's mechanical behavior is predominantly elastic, at least in the strict context of the BAFMD test. Recommendations for potential future research and applications are provided.
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Affiliation(s)
- Bchara Sidnawi
- Department of Mechanical Engineering, Villanova University, PA, 19085, USA; Cellular Biomechanics and Sport Science Laboratory, Villanova University, PA, 19085, USA
| | - Sridhar Santhanam
- Department of Mechanical Engineering, Villanova University, PA, 19085, USA
| | - Chandra Sehgal
- Department of Radiology, University of Pennsylvania, PA, 19104, USA
| | - Qianhong Wu
- Department of Mechanical Engineering, Villanova University, PA, 19085, USA; Cellular Biomechanics and Sport Science Laboratory, Villanova University, PA, 19085, USA.
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36
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Zha D, Fu M, Qian Y. Vascular Endothelial Glycocalyx Damage and Potential Targeted Therapy in COVID-19. Cells 2022; 11:cells11121972. [PMID: 35741101 PMCID: PMC9221624 DOI: 10.3390/cells11121972] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/10/2022] [Accepted: 06/17/2022] [Indexed: 02/06/2023] Open
Abstract
COVID-19 is a highly infectious respiratory disease caused by a new coronavirus known as SARS-CoV-2. COVID-19 is characterized by progressive respiratory failure resulting from diffuse alveolar damage, inflammatory infiltrates, endotheliitis, and pulmonary and systemic coagulopathy forming obstructive microthrombi with multi-organ dysfunction, indicating that endothelial cells (ECs) play a central role in the pathogenesis of COVID-19. The glycocalyx is defined as a complex gel-like layer of glycosylated lipid–protein mixtures, which surrounds all living cells and acts as a buffer between the cell and the extracellular matrix. The endothelial glycocalyx layer (EGL) plays an important role in vascular homeostasis via regulating vascular permeability, cell adhesion, mechanosensing for hemodynamic shear stresses, and antithrombotic and anti-inflammatory functions. Here, we review the new findings that described EGL damage in ARDS, coagulopathy, and the multisystem inflammatory disease associated with COVID-19. Mechanistically, the inflammatory mediators, reactive oxygen species (ROS), matrix metalloproteases (MMPs), the glycocalyx fragments, and the viral proteins may contribute to endothelial glycocalyx damage in COVID-19. In addition, the potential therapeutic strategies targeting the EGL for the treatment of severe COVID-19 are summarized and discussed.
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Affiliation(s)
- Duoduo Zha
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China;
| | - Mingui Fu
- Shock/Trauma Research Center, Department of Biomedical Sciences, School of Medicine, University of Missouri Kansas City, Kansas City, MO 64108, USA;
| | - Yisong Qian
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China;
- Correspondence:
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Milusev A, Rieben R, Sorvillo N. The Endothelial Glycocalyx: A Possible Therapeutic Target in Cardiovascular Disorders. Front Cardiovasc Med 2022; 9:897087. [PMID: 35647072 PMCID: PMC9136230 DOI: 10.3389/fcvm.2022.897087] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 04/21/2022] [Indexed: 12/15/2022] Open
Abstract
The physiological, anti-inflammatory, and anti-coagulant properties of endothelial cells (ECs) rely on a complex carbohydrate-rich layer covering the luminal surface of ECs, called the glycocalyx. In a range of cardiovascular disorders, glycocalyx shedding causes endothelial dysfunction and inflammation, underscoring the importance of glycocalyx preservation to avoid disease initiation and progression. In this review we discuss the physiological functions of the glycocalyx with particular focus on how loss of endothelial glycocalyx integrity is linked to cardiovascular risk factors, like hypertension, aging, diabetes and obesity, and contributes to the development of thrombo-inflammatory conditions. Finally, we consider the role of glycocalyx components in regulating inflammatory responses and discuss possible therapeutic interventions aiming at preserving or restoring the endothelial glycocalyx and therefore protecting against cardiovascular disease.
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Affiliation(s)
- Anastasia Milusev
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, Bern, Switzerland
| | - Robert Rieben
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Nicoletta Sorvillo
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- *Correspondence: Nicoletta Sorvillo
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38
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Holuigue H, Lorenc E, Chighizola M, Schulte C, Varinelli L, Deraco M, Guaglio M, Gariboldi M, Podestà A. Force Sensing on Cells and Tissues by Atomic Force Microscopy. SENSORS (BASEL, SWITZERLAND) 2022; 22:2197. [PMID: 35336366 PMCID: PMC8955449 DOI: 10.3390/s22062197] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/05/2022] [Accepted: 03/09/2022] [Indexed: 01/27/2023]
Abstract
Biosensors are aimed at detecting tiny physical and chemical stimuli in biological systems. Physical forces are ubiquitous, being implied in all cellular processes, including cell adhesion, migration, and differentiation. Given the strong interplay between cells and their microenvironment, the extracellular matrix (ECM) and the structural and mechanical properties of the ECM play an important role in the transmission of external stimuli to single cells within the tissue. Vice versa, cells themselves also use self-generated forces to probe the biophysical properties of the ECM. ECM mechanics influence cell fate, regulate tissue development, and show peculiar features in health and disease conditions of living organisms. Force sensing in biological systems is therefore crucial to dissecting and understanding complex biological processes, such as mechanotransduction. Atomic Force Microscopy (AFM), which can both sense and apply forces at the nanoscale, with sub-nanonewton sensitivity, represents an enabling technology and a crucial experimental tool in biophysics and mechanobiology. In this work, we report on the application of AFM to the study of biomechanical fingerprints of different components of biological systems, such as the ECM, the whole cell, and cellular components, such as the nucleus, lamellipodia and the glycocalyx. We show that physical observables such as the (spatially resolved) Young's Modulus (YM) of elasticity of ECMs or cells, and the effective thickness and stiffness of the glycocalyx, can be quantitatively characterized by AFM. Their modification can be correlated to changes in the microenvironment, physio-pathological conditions, or gene regulation.
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Affiliation(s)
- Hatice Holuigue
- CIMAINA and Dipartimento di Fisica “Aldo Pontremoli”, Università degli Studi di Milano, Via Celoria 16, 20133 Milan, Italy; (H.H.); (E.L.); (M.C.); (C.S.)
| | - Ewelina Lorenc
- CIMAINA and Dipartimento di Fisica “Aldo Pontremoli”, Università degli Studi di Milano, Via Celoria 16, 20133 Milan, Italy; (H.H.); (E.L.); (M.C.); (C.S.)
| | - Matteo Chighizola
- CIMAINA and Dipartimento di Fisica “Aldo Pontremoli”, Università degli Studi di Milano, Via Celoria 16, 20133 Milan, Italy; (H.H.); (E.L.); (M.C.); (C.S.)
| | - Carsten Schulte
- CIMAINA and Dipartimento di Fisica “Aldo Pontremoli”, Università degli Studi di Milano, Via Celoria 16, 20133 Milan, Italy; (H.H.); (E.L.); (M.C.); (C.S.)
| | - Luca Varinelli
- Department of Research, Fondazione IRCCS Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milan, Italy; (L.V.); (M.G.)
| | - Marcello Deraco
- Peritoneal Surface Malignancies Unit, Colorectal Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milan, Italy; (M.D.); (M.G.)
| | - Marcello Guaglio
- Peritoneal Surface Malignancies Unit, Colorectal Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milan, Italy; (M.D.); (M.G.)
| | - Manuela Gariboldi
- Department of Research, Fondazione IRCCS Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milan, Italy; (L.V.); (M.G.)
| | - Alessandro Podestà
- CIMAINA and Dipartimento di Fisica “Aldo Pontremoli”, Università degli Studi di Milano, Via Celoria 16, 20133 Milan, Italy; (H.H.); (E.L.); (M.C.); (C.S.)
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Xia Y, Li Y, Fu BM. Differential effects of vascular endothelial growth factor on glycocalyx of endothelial and tumor cells and potential targets for tumor metastasis. APL Bioeng 2022; 6:016101. [PMID: 35071967 PMCID: PMC8769769 DOI: 10.1063/5.0064381] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 12/20/2021] [Indexed: 11/18/2022] Open
Abstract
On the surface of every mammalian cell, there is a matrix-like glycocalyx (GCX) consisting of proteoglycans and glycosaminoglycans (GAGs). Disruption of endothelial cell (EC) GCX by a vascular endothelial growth factor (VEGF, VEGF-A165), a tumor secretion, was found to be an early event in tumor cell (TC) metastasis across vascular barriers. However, how the TC secretion VEGF affects its own GCX is unknown. To investigate the VEGF effect on TC GCX and to elucidate the ultrastructural organization of EC and TC GCX and their alteration by VEGF, we employed super-resolution stochastic optical reconstruction microscopy to observe the spatio-chemical organizations of the heparan sulfate (HS) and hyaluronic acid (HA), two representative GAGs of GCX, on human cerebral microvascular endothelial cells (hCMEC) and malignant breast cancer cells MDA-MB-231 (MB231). We found that HS and HA have distinct organizations on hCMEC and MB231. Only HS of hCMEC is perpendicular to the cell surface, while HA of hCMEC as well as HS and HA of MB231 all lie in the same plane as the cell surface where they appear to weave into a 2D network covering the cell. We also found that VEGF significantly reduces the length and coverage of HS on hCMEC but does not change the thickness and coverage of HA on hCMEC. On the contrary, VEGF significantly enhances the coverage of HS and HA on MB231 although it does not alter the thickness. The differential effects of VEGF on the GCX of TC and that of EC may favor TC adhesion and transmigration across EC barriers for their metastasis.
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Affiliation(s)
- Yifan Xia
- Department of Biomedical Engineering, The City College of the City University of New York, New York, New York 10031, USA
| | - Yunfei Li
- Department of Biomedical Engineering, The City College of the City University of New York, New York, New York 10031, USA
| | - Bingmei M. Fu
- Department of Biomedical Engineering, The City College of the City University of New York, New York, New York 10031, USA
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40
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Matsuyama S, Tanaka Y, Hasebe R, Hojyo S, Murakami M. Gateway Reflex and Mechanotransduction. Front Immunol 2022; 12:780451. [PMID: 35003096 PMCID: PMC8728022 DOI: 10.3389/fimmu.2021.780451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 11/30/2021] [Indexed: 12/18/2022] Open
Abstract
The gateway reflex explains how autoreactive CD4+ T cells cause inflammation in tissues that have blood-barriers, such as the central nervous system and retina. It depends on neural activations in response to specific external stimuli, such as gravity, pain, stress, and light, which lead to the secretion of noradrenaline at specific vessels in the tissues. Noradrenaline activates NFkB at these vessels, followed by an increase of chemokine expression as well as a reduction of tight junction molecules to accumulate autoreactive CD4+ T cells, which breach blood-barriers. Transient receptor potential vanilloid 1 (TRPV1) molecules on sensory neurons are critical for the gateway reflex, indicating the importance of mechano-sensing. In this review, we overview the gateway reflex with a special interest in mechanosensory transduction (mechanotransduction).
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Affiliation(s)
- Shiina Matsuyama
- Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yuki Tanaka
- Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Group of Quantum Immunology, Institute for Quantum Life Science, National Institute for Quantum and Radiological Science and Technology (QST), Chiba, Japan
| | - Rie Hasebe
- Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Shintaro Hojyo
- Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Group of Quantum Immunology, Institute for Quantum Life Science, National Institute for Quantum and Radiological Science and Technology (QST), Chiba, Japan
| | - Masaaki Murakami
- Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.,Group of Quantum Immunology, Institute for Quantum Life Science, National Institute for Quantum and Radiological Science and Technology (QST), Chiba, Japan.,Division of Neurommunology, National Institute for Physiological Sciences, Okazaki, Japan
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41
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Wu KX, Yeo NJY, Ng CY, Chioh FWJ, Fan Q, Tian X, Yang B, Narayanan G, Tay HM, Hou HW, Dunn NR, Su X, Cheung CMG, Cheung C. Hyaluronidase-1-mediated glycocalyx impairment underlies endothelial abnormalities in polypoidal choroidal vasculopathy. BMC Biol 2022; 20:47. [PMID: 35164755 PMCID: PMC8845246 DOI: 10.1186/s12915-022-01244-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 02/01/2022] [Indexed: 11/11/2022] Open
Abstract
Background Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD), is a global leading cause of vision loss in older populations. Distinct from typical AMD, PCV is characterized by polyp-like dilatation of blood vessels and turbulent blood flow in the choroid of the eye. Gold standard anti-vascular endothelial growth factor (anti-VEGF) therapy often fails to regress polypoidal lesions in patients. Current animal models have also been hampered by their inability to recapitulate such vascular lesions. These underscore the need to identify VEGF-independent pathways in PCV pathogenesis. Results We cultivated blood outgrowth endothelial cells (BOECs) from PCV patients and normal controls to serve as our experimental disease models. When BOECs were exposed to heterogeneous flow, single-cell transcriptomic analysis revealed that PCV BOECs preferentially adopted migratory-angiogenic cell state, while normal BOECs undertook proinflammatory cell state. PCV BOECs also had a repressed protective response to flow stress by demonstrating lower mitochondrial functions. We uncovered that elevated hyaluronidase-1 in PCV BOECs led to increased degradation of hyaluronan, a major component of glycocalyx that interfaces between flow stress and vascular endothelium. Notably, knockdown of hyaluronidase-1 in PCV BOEC improved mechanosensitivity, as demonstrated by a significant 1.5-fold upregulation of Krüppel-like factor 2 (KLF2) expression, a flow-responsive transcription factor. Activation of KLF2 might in turn modulate PCV BOEC migration. Barrier permeability due to glycocalyx impairment in PCV BOECs was also reversed by hyaluronidase-1 knockdown. Correspondingly, hyaluronidase-1 was detected in PCV patient vitreous humor and plasma samples. Conclusions Hyaluronidase-1 inhibition could be a potential therapeutic modality in preserving glycocalyx integrity and endothelial stability in ocular diseases with vascular origin. Supplementary Information The online version contains supplementary material available at 10.1186/s12915-022-01244-z.
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Affiliation(s)
- Kan Xing Wu
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Natalie Jia Ying Yeo
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Chun Yi Ng
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | | | - Qiao Fan
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore.,Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore
| | - Xianfeng Tian
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.,Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Binxia Yang
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Gunaseelan Narayanan
- Institute of Medical Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Hui Min Tay
- School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore, Singapore
| | - Han Wei Hou
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.,School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore, Singapore
| | - N Ray Dunn
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.,School of Biological Sciences Nanyang Technological University, Singapore, Singapore.,Institute of Medical Biology, Agency for Science Technology and Research, Singapore, Singapore
| | - Xinyi Su
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.,Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Singapore Eye Research Institute, Singapore, Singapore.,Department of Ophthalmology, National University Hospital, Singapore, Singapore
| | - Chui Ming Gemmy Cheung
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore.,Singapore Eye Research Institute, Singapore, Singapore
| | - Christine Cheung
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. .,Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
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42
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Ly V, Velichala SR, Hargens AR. Cardiovascular, Lymphatic, and Ocular Health in Space. Life (Basel) 2022; 12:268. [PMID: 35207555 PMCID: PMC8875500 DOI: 10.3390/life12020268] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/22/2022] [Accepted: 02/08/2022] [Indexed: 12/01/2022] Open
Abstract
Life on Earth has evolved continuously under Earth's 1 G force and the protection of the magnetosphere. Thus, astronauts exhibit maladaptive physiological responses during space travel. Exposure to harmful cosmic radiation and weightlessness are unique conditions to the deep-space environment responsible for several spaceflight-associated risks: visual impairment, immune dysfunction, and cancer due to cosmic radiation in astronauts. The evidence thus reviewed indicates that microgravity and cosmic radiation have deleterious effects on the cardiovascular, lymphatic, and vision systems of astronauts on long-duration space missions. The mechanisms responsible for the decline in these systems are potentially due to cytoskeletal filament rearrangement, endothelial dysfunction, and muscular atrophy. These factors may alter fluid hemodynamics within cardiovascular and lymphatic vasculatures such that greater fluid filtration causes facial and intracranial edema. Thus, microgravity induces cephalad fluid shifts contributing to spaceflight-associated neuro-ocular syndrome (SANS). Moreover, visual impairment via retinal ischemia and altered nitric oxide production may alter endothelial function. Based on rodent studies, cosmic radiation may exacerbate the effects of microgravity as observed in impaired endothelium and altered immunity. Relevant findings help understand the extent of these risks associated with spaceflight and suggest relevant countermeasures to protect astronaut health during deep-space missions.
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Affiliation(s)
| | | | - Alan R. Hargens
- Department of Orthopaedic Surgery, UC San Diego Medical Center, University of California San Diego, San Diego, CA 92093, USA; (V.L.); (S.R.V.)
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Triebold C, Barber J. Dependence of red blood cell dynamics in microvessel bifurcations on the endothelial surface layer's resistance to flow and compression. Biomech Model Mechanobiol 2022; 21:771-796. [PMID: 35146594 DOI: 10.1007/s10237-022-01560-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 01/11/2022] [Indexed: 11/30/2022]
Abstract
Red blood cells (RBCs) make up 40-45% of blood and play an important role in oxygen transport. That transport depends on the RBC distribution throughout the body, which is highly heterogeneous. That distribution, in turn, depends on how RBCs are distributed or partitioned at diverging vessel bifurcations where blood flows from one vessel into two. Several studies have used mathematical modeling to consider RBC partitioning at such bifurcations in order to produce useful insights. These studies, however, assume that the vessel wall is a flat impenetrable homogeneous surface. While this is a good first approximation, especially for larger vessels, the vessel wall is typically coated by a flexible, porous endothelial glycocalyx or endothelial surface layer (ESL) that is on the order of 0.5-1 µm thick. To better understand the possible effects of this layer on RBC partitioning, a diverging capillary bifurcation is analyzed using a flexible, two-dimensional model. In addition, the model is also used to investigate RBC deformation and RBC penetration of the ESL region when ESL properties are varied. The RBC is represented using interconnected viscoelastic elements. Stokes flow equations (viscous flow) model the surrounding fluid. The flow in the ESL is modeled using the Brinkman approximation for porous media with a corresponding hydraulic resistivity. The ESL's resistance to compression is modeled using an osmotic pressure difference. One cell passes through the bifurcation at a time, so there are no cell-cell interactions. A range of physiologically relevant hydraulic resistivities and osmotic pressure differences are explored. Decreasing hydraulic resistivity and/or decreasing osmotic pressure differences (ESL resistance to compression) produced four behaviors: (1) RBC partitioning nonuniformity increased slightly; (2) RBC deformation decreased; (3) RBC velocity decreased relative to blood flow velocity; and (4) RBCs penetrated more deeply into the ESL. Decreasing the ESL's resistance to flow and/or compression to pathological levels could lead to more frequent cell adhesion and clotting as well as impaired vascular regulation due to weaker ATP and nitric oxide release. Potential mechanisms that can contribute to these behaviors are also discussed.
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Affiliation(s)
- Carlson Triebold
- Department of Mathematical Sciences, Indiana University - Purdue University Indianapolis, Indianapolis, USA
| | - Jared Barber
- Department of Mathematical Sciences, Indiana University - Purdue University Indianapolis, Indianapolis, USA.
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44
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Masola V, Greco N, Gambaro G, Franchi M, Onisto M. Heparanase as active player in endothelial glycocalyx remodeling. Matrix Biol Plus 2022; 13:100097. [PMID: 35036899 PMCID: PMC8749438 DOI: 10.1016/j.mbplus.2021.100097] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/13/2021] [Accepted: 12/15/2021] [Indexed: 12/11/2022] Open
Abstract
The surface of all animal cells is coated with a layer of carbohydrates linked in various ways to the outer side of the plasma membrane. These carbohydrates are mainly bound to proteins in the form of glycoproteins and proteoglycans and together with the glycolipids constitute the so-called glycocalyx. In particular, the endothelial glycocalyx that covers the luminal layer of the endothelium is composed of glycosaminoglycans (heparan sulphate -HS and hyaluronic acid -HA), proteoglycans (syndecans and glypicans) and adsorbed plasma proteins. Thanks to its ability to absorb water, this structure contributes to making the surface of the vessels slippery but at the same time acts by modulating the mechano-transduction of the vessels, the vascular permeability and the adhesion of leukocytes in thus regulating several physiological and pathological events. Among the various enzymes involved in the degradation of the glycocalyx, heparanase (HPSE) has been shown to be particularly involved. This enzyme is responsible for the cutting of heparan sulfate (HS) chains at the level of the proteoglycans of the endothelial glycocalyx whose dysfunction appears to have a role in organ fibrosis, sepsis and viral infection. In this mini-review, we describe the mechanisms by which HPSE contributes to glycocalyx remodeling and then examine the role of glycocalyx degradation in the development of pathological conditions and pharmacological strategies to preserve glycocalyx during disease pathogenesis.
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Affiliation(s)
- Valentina Masola
- Renal Unit, Dept. of Medicine, University Hospital of Verona, Verona, Italy.,Dept. of Biomedical Sciences, University of Padova, Padua, Italy
| | - Nicola Greco
- Dept. of Biomedical Sciences, University of Padova, Padua, Italy
| | - Giovanni Gambaro
- Renal Unit, Dept. of Medicine, University Hospital of Verona, Verona, Italy
| | - Marco Franchi
- Dept. of Life Quality Sciences, University of Bologna, Rimini, Italy
| | - Maurizio Onisto
- Dept. of Biomedical Sciences, University of Padova, Padua, Italy
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45
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Effect of Ulinastatin on Syndecan-2-Mediated Vascular Damage in IDH2-Deficient Endothelial Cells. Biomedicines 2022; 10:biomedicines10010187. [PMID: 35052866 PMCID: PMC8774120 DOI: 10.3390/biomedicines10010187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/13/2022] [Accepted: 01/14/2022] [Indexed: 12/07/2022] Open
Abstract
Syndecan-2 (SDC2), a cell-surface heparin sulfate proteoglycan of the glycocalyx, is mainly expressed in endothelial cells. Although oxidative stress and inflammatory mediators have been shown to mediate dysfunction of the glycocalyx, little is known about their role in vascular endothelial cells. In this study, we aimed to identify the mechanism that regulates SDC2 expression in isocitrate dehydrogenase 2 (IDH2)-deficient endothelial cells, and to investigate the effect of ulinastatin (UTI) on this mechanism. We showed that knockdown of IDH2 induced SDC2 expression in human umbilical vein endothelial cells (HUVECs). Matrix metalloproteinase 7 (MMP7) influences SDC2 expression. When IDH2 was downregulated, MMP7 expression was increased, as was TGF-β signaling, which regulates MMP7. Inhibition of MMP7 activity using MMP inhibitor II significantly reduced SDC2, suggesting that IDH2 mediated SDC2 expression via MMP7. Moreover, expression of SDC2 and MMP7, as well as TGF-β signaling, increased in response to IDH2 deficiency, and treatment with UTI reversed this increase. Similarly, the increase in SDC2, MMP7, and TGF-β signaling in the aorta of IDH2 knockout mice was reversed by UTI treatment. These findings suggest that IDH2 deficiency induces SDC2 expression via TGF-β and MMP7 signaling in endothelial cells.
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46
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Xia Y, Li Y, Khalid W, Bikson M, Fu BM. Direct Current Stimulation Disrupts Endothelial Glycocalyx and Tight Junctions of the Blood-Brain Barrier in vitro. Front Cell Dev Biol 2021; 9:731028. [PMID: 34650977 PMCID: PMC8505730 DOI: 10.3389/fcell.2021.731028] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 09/08/2021] [Indexed: 01/01/2023] Open
Abstract
Transcranial direct current stimulation (tDCS) is a non-invasive physical therapy to treat many psychiatric disorders and to enhance memory and cognition in healthy individuals. Our recent studies showed that tDCS with the proper dosage and duration can transiently enhance the permeability (P) of the blood-brain barrier (BBB) in rat brain to various sized solutes. Based on the in vivo permeability data, a transport model for the paracellular pathway of the BBB also predicted that tDCS can transiently disrupt the endothelial glycocalyx (EG) and the tight junction between endothelial cells. To confirm these predictions and to investigate the structural mechanisms by which tDCS modulates P of the BBB, we directly quantified the EG and tight junctions of in vitro BBB models after DCS treatment. Human cerebral microvascular endothelial cells (hCMECs) and mouse brain microvascular endothelial cells (bEnd3) were cultured on the Transwell filter with 3 μm pores to generate in vitro BBBs. After confluence, 0.1–1 mA/cm2 DCS was applied for 5 and 10 min. TEER and P to dextran-70k of the in vitro BBB were measured, HS (heparan sulfate) and hyaluronic acid (HA) of EG was immuno-stained and quantified, as well as the tight junction ZO-1. We found disrupted EG and ZO-1 when P to dextran-70k was increased and TEER was decreased by the DCS. To further investigate the cellular signaling mechanism of DCS on the BBB permeability, we pretreated the in vitro BBB with a nitric oxide synthase (NOS) inhibitor, L-NMMA. L-NMMA diminished the effect of DCS on the BBB permeability by protecting the EG and reinforcing tight junctions. These in vitro results conform to the in vivo observations and confirm the model prediction that DCS can disrupt the EG and tight junction of the BBB. Nevertheless, the in vivo effects of DCS are transient which backup its safety in the clinical application. In conclusion, our current study directly elucidates the structural and signaling mechanisms by which DCS modulates the BBB permeability.
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Affiliation(s)
- Yifan Xia
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY, United States
| | - Yunfei Li
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY, United States
| | - Wasem Khalid
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY, United States
| | - Marom Bikson
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY, United States
| | - Bingmei M Fu
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY, United States
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47
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Li Y, Xia Y, Zhu H, Luu E, Huang G, Sun Y, Sun K, Markx S, Leong KW, Xu B, Fu BM. Investigation of Neurodevelopmental Deficits of 22 q11.2 Deletion Syndrome with a Patient-iPSC-Derived Blood-Brain Barrier Model. Cells 2021; 10:cells10102576. [PMID: 34685556 PMCID: PMC8534009 DOI: 10.3390/cells10102576] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/24/2021] [Accepted: 09/26/2021] [Indexed: 12/13/2022] Open
Abstract
The blood–brain barrier (BBB) is important in the normal functioning of the central nervous system. An altered BBB has been described in various neuropsychiatric disorders, including schizophrenia. However, the cellular and molecular mechanisms of such alterations remain unclear. Here, we investigate if BBB integrity is compromised in 22q11.2 deletion syndrome (also called DiGeorge syndrome), which is one of the validated genetic risk factors for schizophrenia. We utilized a set of human brain microvascular endothelial cells (HBMECs) derived from the induced pluripotent stem cell (iPSC) lines of patients with 22q11.2-deletion-syndrome-associated schizophrenia. We found that the solute permeability of the BBB formed from patient HBMECs increases by ~1.3–1.4-fold, while the trans-endothelial electrical resistance decreases to ~62% of the control values. Correspondingly, tight junction proteins and the endothelial glycocalyx that determine the integrity of the BBB are significantly disrupted. A transcriptome study also suggests that the transcriptional network related to the cell–cell junctions in the compromised BBB is substantially altered. An enrichment analysis further suggests that the genes within the altered gene expression network also contribute to neurodevelopmental disorders. Our findings suggest that neurovascular coupling can be targeted in developing novel therapeutical strategies for the treatment of 22q11.2 deletion syndrome.
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Affiliation(s)
- Yunfei Li
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA; (Y.L.); (Y.X.); (E.L.); (G.H.)
| | - Yifan Xia
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA; (Y.L.); (Y.X.); (E.L.); (G.H.)
| | - Huixiang Zhu
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; (H.Z.); (Y.S.); (K.S.); (S.M.)
| | - Eric Luu
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA; (Y.L.); (Y.X.); (E.L.); (G.H.)
| | - Guangyao Huang
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA; (Y.L.); (Y.X.); (E.L.); (G.H.)
| | - Yan Sun
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; (H.Z.); (Y.S.); (K.S.); (S.M.)
| | - Kevin Sun
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; (H.Z.); (Y.S.); (K.S.); (S.M.)
| | - Sander Markx
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; (H.Z.); (Y.S.); (K.S.); (S.M.)
| | - Kam W. Leong
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA;
| | - Bin Xu
- Department of Psychiatry, Columbia University, New York, NY 10032, USA; (H.Z.); (Y.S.); (K.S.); (S.M.)
- Correspondence: (B.X.); (B.M.F.); Tel.: +1-212-650-7531 (B.M.F.)
| | - Bingmei M. Fu
- Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA; (Y.L.); (Y.X.); (E.L.); (G.H.)
- Correspondence: (B.X.); (B.M.F.); Tel.: +1-212-650-7531 (B.M.F.)
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48
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Li J, Fang Y, Wu D. Mechanical forces and metabolic changes cooperate to drive cellular memory and endothelial phenotypes. CURRENT TOPICS IN MEMBRANES 2021; 87:199-253. [PMID: 34696886 PMCID: PMC8639155 DOI: 10.1016/bs.ctm.2021.07.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Endothelial cells line the innermost layer of arterial, venous, and lymphatic vascular tree and accordingly are subject to hemodynamic, stretch, and stiffness mechanical forces. Normally quiescent, endothelial cells have a hemodynamic set point and become "activated" in response to disturbed hemodynamics, which may signal impending nutrient or gas depletion. Endothelial cells in the majority of tissue beds are normally inactivated and maintain vessel barrier functions, are anti-inflammatory, anti-coagulant, and anti-thrombotic. However, under aberrant mechanical forces, endothelial signaling transforms in response, resulting cellular changes that herald pathological diseases. Endothelial cell metabolism is now recognized as the primary intermediate pathway that undergirds cellular transformation. In this review, we discuss the various mechanical forces endothelial cells sense in the large vessels, microvasculature, and lymphatics, and how changes in environmental mechanical forces result in changes in metabolism, which ultimately influence cell physiology, cellular memory, and ultimately disease initiation and progression.
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Affiliation(s)
- Jin Li
- Committee on Molecular Metabolism and Nutrition, Biological Sciences Division, University of Chicago, Chicago, IL, United States; Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL, United States
| | - Yun Fang
- Committee on Molecular Metabolism and Nutrition, Biological Sciences Division, University of Chicago, Chicago, IL, United States; Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL, United States
| | - David Wu
- Committee on Molecular Metabolism and Nutrition, Biological Sciences Division, University of Chicago, Chicago, IL, United States; Department of Medicine, Biological Sciences Division, University of Chicago, Chicago, IL, United States.
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49
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Santa-Maria AR, Walter FR, Figueiredo R, Kincses A, Vigh JP, Heymans M, Culot M, Winter P, Gosselet F, Dér A, Deli MA. Flow induces barrier and glycocalyx-related genes and negative surface charge in a lab-on-a-chip human blood-brain barrier model. J Cereb Blood Flow Metab 2021; 41:2201-2215. [PMID: 33563079 PMCID: PMC8393308 DOI: 10.1177/0271678x21992638] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Microfluidic lab-on-a-chip (LOC) devices allow the study of blood-brain barrier (BBB) properties in dynamic conditions. We studied a BBB model, consisting of human endothelial cells derived from hematopoietic stem cells in co-culture with brain pericytes, in an LOC device to study fluid flow in the regulation of endothelial, BBB and glycocalyx-related genes and surface charge. The highly negatively charged endothelial surface glycocalyx functions as mechano-sensor detecting shear forces generated by blood flow on the luminal side of brain endothelial cells and contributes to the physical barrier of the BBB. Despite the importance of glycocalyx in the regulation of BBB permeability in physiological conditions and in diseases, the underlying mechanisms remained unclear. The MACE-seq gene expression profiling analysis showed differentially expressed endothelial, BBB and glycocalyx core protein genes after fluid flow, as well as enriched pathways for the extracellular matrix molecules. We observed increased barrier properties, a higher intensity glycocalyx staining and a more negative surface charge of human brain-like endothelial cells (BLECs) in dynamic conditions. Our work is the first study to provide data on BBB properties and glycocalyx of BLECs in an LOC device under dynamic conditions and confirms the importance of fluid flow for BBB culture models.
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Affiliation(s)
- Ana R Santa-Maria
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary.,Doctoral School of Biology, University of Szeged, Szeged, Hungary.,Department of Biotechnology, University of Szeged, Szeged, Hungary
| | - Fruzsina R Walter
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary.,Department of Biotechnology, University of Szeged, Szeged, Hungary
| | - Ricardo Figueiredo
- GenXPro GmbH, Frankfurt-Am-Main, Germany.,Johann Wolfgang Goethe University, Frankfurt, Frankfurt-Am-Main, Germany
| | - András Kincses
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary.,Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, Hungary
| | - Judit P Vigh
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary.,Doctoral School of Biology, University of Szeged, Szeged, Hungary
| | - Marjolein Heymans
- Université d'Artois, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Lens, France
| | - Maxime Culot
- Université d'Artois, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Lens, France
| | | | - Fabien Gosselet
- Université d'Artois, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Lens, France
| | - András Dér
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary
| | - Mária A Deli
- Institute of Biophysics, Biological Research Centre, Szeged, Hungary
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50
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Sidnawi B, Chen Z, Sehgal C, Santhanam S, Wu Q. On the modeling of mechanotransduction in flow-mediated dilation. J Mech Behav Biomed Mater 2021; 120:104606. [PMID: 34044251 PMCID: PMC11139487 DOI: 10.1016/j.jmbbm.2021.104606] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 11/17/2022]
Abstract
In this paper, we report a physics based mathematical model to describe the mechanotransduction at the luminal surface of the brachial artery during a flow-mediated dilation (FMD) process. To account for the effect of the released vasodilators in response to the sudden blood flow resurgence, a scalar property is introduced as a signal radially diffusing through the arterial wall, locally affecting its compliance. The model was evaluated on 19 in vivo responses of brachial artery FMD (BAFMD) in 12 healthy subjects. It successfully reproduces the time-dependent dilation of the brachial artery. The predicted artery's outer-to-inner radius ratio was also found to be consistent with the measurements within an acceptable margin of error. Physically meaningful dimensionless parameters quantifying the artery's physical state arose from the model, providing a description to how sensitive or responsive the artery is to the changes of wall shear stress (WSS). Future applications of this model, via incorporating inexpensive, relatively quick, and non-invasive imaging, could potentially help detect early stages of developing forms of cardiovascular diseases.
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Affiliation(s)
- Bchara Sidnawi
- Department of Mechanical Engineering, Villanova University, PA, 19085, USA; Cellular Biomechanics and Sport Science Laboratory, Villanova University, PA, 19085, USA
| | - Zhen Chen
- Department of Radiology, University of Pennsylvania, PA, 19104, USA
| | - Chandra Sehgal
- Department of Radiology, University of Pennsylvania, PA, 19104, USA
| | - Sridhar Santhanam
- Department of Mechanical Engineering, Villanova University, PA, 19085, USA
| | - Qianhong Wu
- Department of Mechanical Engineering, Villanova University, PA, 19085, USA; Cellular Biomechanics and Sport Science Laboratory, Villanova University, PA, 19085, USA.
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