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Jo DH, Kim JH. Toward the Clinical Application of Therapeutic Angiogenesis Against Pediatric Ischemic Retinopathy. J Lipid Atheroscler 2020; 9:268-282. [PMID: 32821736 PMCID: PMC7379088 DOI: 10.12997/jla.2020.9.2.268] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/29/2020] [Accepted: 05/13/2020] [Indexed: 11/13/2022] Open
Abstract
Therapeutic angiogenesis refers to strategies of inducing angiogenesis to treat diseases involving ischemic conditions. Historically, most attempts and achievements have been related to coronary and peripheral artery diseases. In this review, we propose the clinical application of therapeutic angiogenesis for the treatment of pediatric ischemic retinopathy, including retinopathy of prematurity, familial exudative retinopathy, and NDP-related retinopathy. These diseases are all characterized by the reduction of physiological angiogenesis and the following induction of pathological angiogenesis. Therapeutic angiogenesis, which supplements insufficient physiological angiogenesis, may be a therapeutic approach for ischemic conditions. Various molecules and modalities can be utilized to apply therapeutic angiogenesis for the treatment of ischemic retinopathy, as in coronary and peripheral artery diseases. Experiences with cardiovascular diseases provide a useful reference for the further clinical application of therapeutic angiogenesis in pediatric ischemic retinopathy. Recombinant proteins and gene therapy are powerful tools to deliver angiogenic factors to retinal tissues directly. Furthermore, endothelial progenitor or bone marrow-derived cells can be injected into the vitreous cavity of the eye for therapeutic angiogenesis. Intraocular injections are highly promising for the delivery of therapeutics for therapeutic angiogenesis. We expect that therapeutic angiogenesis will be a breakthrough in the treatment of pediatric ischemic retinopathy.
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Affiliation(s)
- Dong Hyun Jo
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Hun Kim
- Fight against Angiogenesis-Related Blindness, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.,Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.,Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea
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Rammos C, Luedike P, Hendgen-Cotta U, Rassaf T. Potential of dietary nitrate in angiogenesis. World J Cardiol 2015; 7:652-657. [PMID: 26516419 PMCID: PMC4620076 DOI: 10.4330/wjc.v7.i10.652] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Revised: 08/12/2015] [Accepted: 09/16/2015] [Indexed: 02/06/2023] Open
Abstract
Endothelial dysfunction with impaired bioavailability of nitric oxide (NO) is the hallmark in the development of cardiovascular disease. Endothelial dysfunction leads to atherosclerosis, characterized by chronic inflammation of the arterial wall and stepwise narrowing of the vessel lumen. Atherosclerosis causes deprivation of adequate tissue blood flow with compromised oxygen supply. To overcome this undersupply, remodeling of the vascular network is necessary to reconstitute and sustain tissue viability. This physiological response is often not sufficient and therapeutic angiogenesis remains an unmet medical need in critical limb ischemia or coronary artery disease. Feasible approaches to promote blood vessel formation are sparse. Administration of pro-angiogenic factors, gene therapy, or targeting of microRNAs has not yet entered the daily practice. Nitric oxide is an important mediator of angiogenesis that becomes limited under ischemic conditions and the maintenance of NO availability might constitute an attractive therapeutic target. Until recently it was unknown how the organism provides NO under ischemia. In recent years it could be demonstrated that NO can be formed independently of its enzymatic synthesis in the endothelium by reduction of inorganic nitrite under hypoxic conditions. Circulating nitrite derives from oxidation of NO or reduction of inorganic nitrate by commensal bacteria in the oral cavity. Intriguingly, nitrate is a common constituent of our everyday diet and particularly high concentrations are found in leafy green vegetables such as spinach, lettuce, or beetroot. Evidence suggests that dietary nitrate supplementation increases the regenerative capacity of ischemic tissue and that this effect may offer an attractive nutrition-based strategy to improve ischemia-induced revascularization. We here summarize and discuss the regenerative capacity of dietary nitrate on the vascular system.
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Joshi D, Abraham D, Shiwen X, Baker D, Tsui J. Potential role of erythropoietin receptors and ligands in attenuating apoptosis and inflammation in critical limb ischemia. J Vasc Surg 2013; 60:191-201, 201.e1-2. [PMID: 24055514 DOI: 10.1016/j.jvs.2013.06.054] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Revised: 05/23/2013] [Accepted: 06/03/2013] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Managing critical limb ischemia (CLI) is challenging. Furthermore, ischemic myopathy prevents good functional outcome after revascularization. Hence, we have focused on limiting the tissue damage rather than angiogenesis, which has traditionally been the motivation to develop nonsurgical treatments for CLI. Erythropoietin (EPO) protects ischemic tissue, and this property may also benefit CLI. The objective of this study was to examine the expression of the tissue-protective EPO receptor complex (EPOR-CD131 [β-chain of interleukin (IL)-3/IL-5/granulocyte macrophage colony-stimulating factor receptor]) in skeletal muscle obtained from humans with CLI. Because native EPO is thrombogenic, the antiapoptotic and anti-inflammatory effects of a nonhematopoietic helix-B peptide of EPO (ARA 290) were investigated on ischemic myotubes in vitro. METHODS Tissue was obtained from gastrocnemius muscle of 12 patients undergoing amputation for CLI and from 12 patients without limb ischemia. The expression of EPOR and CD131 was demonstrated by immunohistochemistry and Western blot. A validated in vitro model of myotube ischemia was used in which mature C2C12 myotubes were cultured 6 to 12 hours in a depleted media and gas mixture (20% CO2 and 80% N2). The myotubes were pretreated with EPO or ARA 290 before exposure to simulated ischemia. Apoptosis and cell death were determined by cleaved caspase-3 assay and lactate dehydrogenase release assay. Enzyme-linked immunosorbent assay measured the inflammatory cytokines. RESULTS EPOR and CD131 were expressed and significantly upregulated in CLI (average optical density [OD] in Western blot [control vs CLI] EPOR, 0.05 U vs 0.1 U; CD131, 0.10 U vs 0.22 U; P < .01). There was colocalization of EPOR and CD131 in the sarcolemma (cell membrane) of the skeletal myofiber. There was no difference in the distribution of colocalization between the CLI and the normal muscle. The ischemic myotubes treated by ARA 290 in vitro had a significantly decreased number of apoptotic cells (ischemia vs ischemia plus ARA 290: 71.1% vs 55.1%; P < .01), cleaved caspase-3 (OD of ischemia vs ischemia plus ARA 290: 0.15 U vs 0.02 U; P < .01), lactate dehydrogenase release (ischemia vs ischemia plus ARA 290: 32.5 U/L vs 21.3 U/L; P < .01), and IL-6 release (OD at 450 nm, ischemia vs ischemia plus ARA 290: 0.18 vs 0.13; P < .01). CONCLUSIONS This study demonstrates the expression and the upregulation of EPOR and CD131 in CLI and also shows that EPOR and CDI are colocalized in the cell membrane of both ischemic and control muscle fiber. The in vitro experiments demonstrate that ARA 290 decreases inflammation and apoptosis of ischemic myotubes. ARA 290 may potentially be used as adjunctive treatment for CLI.
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Affiliation(s)
- Dhiraj Joshi
- Royal Free Vascular Unit, Division of Surgery & Interventional Science, University College London, London, United Kingdom
| | - David Abraham
- Centre for Rheumatology and Connective Tissue Disease, University College London, London, United Kingdom
| | - Xu Shiwen
- Centre for Rheumatology and Connective Tissue Disease, University College London, London, United Kingdom
| | - Daryl Baker
- Royal Free Vascular Unit, Division of Surgery & Interventional Science, University College London, London, United Kingdom
| | - Janice Tsui
- Royal Free Vascular Unit, Division of Surgery & Interventional Science, University College London, London, United Kingdom.
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Hendgen-Cotta UB, Luedike P, Totzeck M, Kropp M, Schicho A, Stock P, Rammos C, Niessen M, Heiss C, Lundberg JO, Weitzberg E, Kelm M, Rassaf T. Dietary nitrate supplementation improves revascularization in chronic ischemia. Circulation 2012; 126:1983-92. [PMID: 22992322 DOI: 10.1161/circulationaha.112.112912] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Revascularization is an adaptive repair mechanism that restores blood flow to undersupplied ischemic tissue. Nitric oxide plays an important role in this process. Whether dietary nitrate, serially reduced to nitrite by commensal bacteria in the oral cavity and subsequently to nitric oxide and other nitrogen oxides, enhances ischemia-induced remodeling of the vascular network is not known. METHODS AND RESULTS Mice were treated with either nitrate (1 g/L sodium nitrate in drinking water) or sodium chloride (control) for 14 days. At day 7, unilateral hind-limb surgery with excision of the left femoral artery was conducted. Blood flow was determined by laser Doppler. Capillary density, myoblast apoptosis, mobilization of CD34(+)/Flk-1(+), migration of bone marrow-derived CD31(+)/CD45(-), plasma S-nitrosothiols, nitrite, and skeletal tissue cGMP levels were assessed. Enhanced green fluorescence protein transgenic mice were used for bone marrow transplantation. Dietary nitrate increased plasma S-nitrosothiols and nitrite, enhanced revascularization, increased mobilization of CD34(+)/Flk-1(+) and migration of bone marrow-derived CD31(+)/CD45(-) cells to the site of ischemia, and attenuated apoptosis of potentially regenerative myoblasts in chronically ischemic tissue. The regenerative effects of nitrate treatment were abolished by eradication of the nitrate-reducing bacteria in the oral cavity through the use of an antiseptic mouthwash. CONCLUSIONS Long-term dietary nitrate supplementation may represent a novel nutrition-based strategy to enhance ischemia-induced revascularization.
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Affiliation(s)
- Ulrike B Hendgen-Cotta
- Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
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Joshi D, Tsui J, Yu R, Shiwen X, Selvakumar S, Abraham DJ, Baker DM. Potential of Novel EPO Derivatives in Limb Ischemia. Cardiol Res Pract 2012; 2012:213785. [PMID: 22462027 PMCID: PMC3296231 DOI: 10.1155/2012/213785] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Accepted: 12/12/2011] [Indexed: 12/18/2022] Open
Abstract
Erythropoietin (EPO) has tissue-protective properties, but it increases the risk of thromboembolism by raising the haemoglobin concentration. New generation of EPO derivatives is tissue protective without the haematopoietic side effects. Preclinical studies have demonstrated their effectiveness and safety. This paper summarizes the development in EPO derivatives with emphasis on their potential use in critical limb ischaemia.
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Affiliation(s)
- Dhiraj Joshi
- Vascular Unit, Division of Surgery and Interventional Science, Royal Free Hospital, University College London (Royal Free Campus), Pond Street, London NW3 2QG, UK
| | - Janice Tsui
- Vascular Unit, Division of Surgery and Interventional Science, Royal Free Hospital, University College London (Royal Free Campus), Pond Street, London NW3 2QG, UK
| | - Rebekah Yu
- Vascular Unit, Division of Surgery and Interventional Science, Royal Free Hospital, University College London (Royal Free Campus), Pond Street, London NW3 2QG, UK
| | - Xu Shiwen
- Centre for Rheumatology, University College London (Royal Free Campus), Pond Street, London NW3 2QG, UK
| | - Sadasivam Selvakumar
- Vascular Unit, Division of Surgery and Interventional Science, Royal Free Hospital, University College London (Royal Free Campus), Pond Street, London NW3 2QG, UK
| | - David J. Abraham
- Centre for Rheumatology, University College London (Royal Free Campus), Pond Street, London NW3 2QG, UK
| | - Daryll M. Baker
- Vascular Unit, Division of Surgery and Interventional Science, Royal Free Hospital, University College London (Royal Free Campus), Pond Street, London NW3 2QG, UK
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The importance of hypoxia-regulated, RPE-targeted gene therapy for choroidal neovascularization. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 723:269-77. [PMID: 22183342 DOI: 10.1007/978-1-4614-0631-0_35] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Abstract
Cardiovascular pathologies are still the primary cause of death worldwide. The molecular mechanisms behind these pathologies have not been fully elucidated. Unravelling them will bring us closer to therapeutic strategies to prevent or treat cardiovascular disease. One of the major transcription factors that has been linked to both cardiovascular health and disease is NF-kappaB (nuclear factor kappaB). The NF-kappaB family controls multiple processes, including immunity, inflammation, cell survival, differentiation and proliferation, and regulates cellular responses to stress, hypoxia, stretch and ischaemia. It is therefore not surprising that NF-kappaB has been shown to influence numerous cardiovascular diseases including atherosclerosis, myocardial ischaemia/reperfusion injury, ischaemic preconditioning, vein graft disease, cardiac hypertrophy and heart failure. The function of NF-kappaB is largely dictated by the genes that it targets for transcription and varies according to stimulus and cell type. Thus NF-kappaB has divergent functions and can protect cardiovascular tissues from injury or contribute to pathogenesis depending on the cellular and physiological context. The present review will focus on recent studies on the function of NF-kappaB in the cardiovascular system.
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Birkenhauer P, Yang Z, Gander B. Preventing restenosis in early drug-eluting stent era: recent developments and future perspectives. J Pharm Pharmacol 2010; 56:1339-56. [PMID: 15525440 DOI: 10.1211/0022357044797] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Abstract
Restenosis is the major limitation of the successful therapy of percutaneous coronary intervention (PCI) for patients with coronary artery disease. The problem was appreciated in the late 1970s to early 1980s. Only in recent years, anti-restenotic therapy has achieved a breakthrough with the development of drug-eluting stents. Here, we provide an overview about pathological mechanisms of restenosis after PCI. Present therapeutic approaches to overcome restenosis and recent clinical results are revisited, and some major concerns in the post-drug-eluting stent era are discussed.
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Affiliation(s)
- Peter Birkenhauer
- Institute of Pharmaceutical Sciences, ETH Hönggerberg HCI, 8093 Zürich, Switzerland
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Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis. Proc Natl Acad Sci U S A 2008; 105:7540-5. [PMID: 18508974 DOI: 10.1073/pnas.0711480105] [Citation(s) in RCA: 155] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Chronic tissue ischemia due to defective vascular perfusion is a hallmark feature of peripheral artery disease for which minimal therapeutic options exist. We have reported that sodium nitrite therapy exerts cytoprotective effects against acute ischemia/reperfusion injury in both heart and liver, consistent with the model of bioactive NO formation from nitrite during ischemic stress. Here, we test the hypothesis that chronic sodium nitrite therapy can selectively augment angiogenic activity and tissue perfusion in the murine hind-limb ischemia model. Various therapeutic doses (8.25-3,300 mug/kg) of sodium nitrite or PBS were administered. Sodium nitrite significantly restored ischemic hind-limb blood flow in a time-dependent manner, with low-dose sodium nitrite being most effective. Nitrite therapy significantly increased ischemic limb vascular density and stimulated endothelial cell proliferation. Remarkably, the effects of sodium nitrite therapy were evident within 3 days of the ischemic insult demonstrating the potency and efficacy of chronic sodium nitrite therapy. Sodium nitrite therapy also increased ischemic tissue nitrite and NO metabolites compared to nonischemic limbs. Use of the NO scavenger carboxy PTIO completely abolished sodium nitrite-dependent ischemic tissue blood flow and angiogenic activity consistent with nitrite reduction to NO being the proangiogenic mechanism. These data demonstrate that chronic sodium nitrite therapy is a recently discovered therapeutic treatment for peripheral artery disease and critical limb ischemia.
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Abstract
Hypoxia and its corollaries pose both negative and positive pressures to multicellular eukaryotes. Evolutionarily, life developed under hypoxia, and the building blocks were established under conditions close to anaerobiosis; therefore, reason exists to expect that certain biologic processes may perform preferentially under hypoxia. Evolving evidence suggests that by providing an environment of reduced oxidative stress, hypoxia may help preserve the biologic functions of some cells and prevent senescence. Hypoxia provides essential signals for development, trimming redundant tissue by inducing apoptosis and driving the growth and development of oxygen and nutrient delivery systems, as well as those for waste management. The pathologic consequences of hypoxia and ischemia, including acidosis and oxidative stress associated with hypoxia-reoxygenation, form the basis of most of the major diseases confronting humans, including heart disease, cancer, and age-related degenerative conditions. The 11 articles in the forum touch on multiple aspects of hypoxia, in particular, signaling responses, adaptations, and diseases that result from imbalance and fluctuations of supply and demand. Although we have developed elaborate processes to combat hypoxia and oxidative damage, it is clear that oxygen and our environment still control us, perhaps even more than they did our unicellular ancestors 2 billion years ago.
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11
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Frazier DP, Wilson A, Dougherty CJ, Li H, Bishopric NH, Webster KA. PKC-α and TAK-1 are intermediates in the activation ofc-Jun NH2-terminal kinase by hypoxia-reoxygenation. Am J Physiol Heart Circ Physiol 2007; 292:H1675-84. [PMID: 17209006 DOI: 10.1152/ajpheart.01132.2006] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
c-Jun NH2-terminal kinase (JNK), a member of the MAPK family of protein kinases, is a stress-response kinase that is activated by proinflammatory cytokines and growth factors coupled to membrane receptors or through nonreceptor pathways by stimuli such as heat shock, UV irradiation, protein synthesis inhibitors, and conditions that elevate the levels of reactive oxygen intermediates (ROI). Ischemia followed by reperfusion or hypoxia with reoxygenation represents a condition of high oxidative stress where JNK activation is associated with elevated ROI. We recently demonstrated that the activation of JNK by this condition is initiated by ROI generated by mitochondrial electron transport and involves sequential activation of the proline-rich kinase 2 and the small GTP-binding factors Rac-1 and Cdc42. Here we present evidence that protein kinase C (PKC) and transforming growth factor-β-activated kinase-1 (TAK-1) are also components of this pathway. Inhibition of PKC with the broad-range inhibitor calphostin C, the PKC-α/β-selective inhibitor Go9367, or adenovirus-expressing dominant-negative PKC-α blocked the phosphorylation of proline-rich kinase 2 and JNK. Reoxygenation activated the mitogen-activated protein kinase kinase kinase, TAK-1, and promoted the formation of a complex containing Rac-1, TAK-1, and JNK but not apoptosis-stimulating kinase-1 or p21-activated kinase-1, which was detected within the first 10 min of reoxygenation. These results identify two new components, PKC and TAK-1, that have not been previously described in this signaling pathway.
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Affiliation(s)
- Donna P Frazier
- Department of Molecular and Cellular Pharmacology, Vascular Biology Institute, University of Miami School of Medicine, Miami, Florida 33136, USA
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12
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Wang Y, Zhen Y, Shi Y, Chen J, Zhang C, Wang X, Yang X, Zheng Y, Liu Y, Hui R. Vitamin k epoxide reductase: a protein involved in angiogenesis. Mol Cancer Res 2005; 3:317-23. [PMID: 15972850 DOI: 10.1158/1541-7786.mcr-04-0221] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Vitamin K epoxide reductase (VKOR) is a newly identified protein which has been reported to convert the epoxide of vitamin K back to vitamin K, a cofactor essential for the posttranslational gamma-carboxylation of several blood coagulation factors. We found that the gene is expressed ubiquitously including vascular endothelial cells, smooth muscle cells, fibroblasts and cardiomyocytes, and is overexpressed in 11 tumor tissues on microarray. Stable transfection of VKOR cDNA into tumor cell line A549 and H7402 did not promote the cell proliferation. These results promoted us to hypothesize that VKOR may also be involved in angiogenesis. To test this hypothesis, the expression of VKOR was studied in different vascular cells in developmental and pathologic heart tissues. The effects of overexpression and suppressing expression of VKOR on endothelial cell proliferation, migration, adhesion, and tubular network formation were explored. We found that VKOR expression in arteries was prominent in vascular endothelial cells and was high in the ventricular aneurysm tissue of human heart and human fetal heart. In vitro studies showed that overexpression of VKOR slightly but significantly stimulated human umbilical vein endothelial cell proliferation (by 120%), migration (by 118%), adhesion (by 117%), as well as tubular network formation. Antisense to VKOR gene inhibited the proliferation (by 67%), migration (by 64%), adhesion (by 50%), and tubular network formation. Our findings support the impact of VKOR in the process of angiogenesis; hence, the molecule may have a potential application in cardiovascular disease and cancer therapy.
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MESH Headings
- Adenoviridae/genetics
- Aneurysm/enzymology
- Aneurysm/metabolism
- Aneurysm/pathology
- Aorta/cytology
- Cell Adhesion/drug effects
- Cell Line
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Dose-Response Relationship, Drug
- Endothelium, Vascular/cytology
- Endothelium, Vascular/metabolism
- Fetus
- Gene Expression Regulation
- Heart Ventricles/metabolism
- Heart Ventricles/pathology
- Humans
- Mixed Function Oxygenases/genetics
- Mixed Function Oxygenases/metabolism
- Muscle, Smooth, Vascular/enzymology
- Muscle, Smooth, Vascular/metabolism
- Myocardium/enzymology
- Myocardium/metabolism
- Neovascularization, Physiologic/physiology
- Oligonucleotides, Antisense/pharmacology
- Organogenesis/drug effects
- Proteins/genetics
- Proteins/metabolism
- RNA, Messenger/metabolism
- Tissue Distribution
- Transfection
- Umbilical Veins/cytology
- Vascular Endothelial Growth Factor A/pharmacology
- Vitamin K Epoxide Reductases
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Affiliation(s)
- Yibo Wang
- Sino-German Laboratory for Molecular Medicine and Hypertension Division, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Xicheng District, Beijing 100037, P.R. China
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13
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Gounis MJ, Spiga MG, Graham RM, Wilson A, Haliko S, Lieber BB, Wakhloo AK, Webster KA. Angiogenesis is confined to the transient period of VEGF expression that follows adenoviral gene delivery to ischemic muscle. Gene Ther 2005; 12:762-71. [PMID: 15772688 DOI: 10.1038/sj.gt.3302481] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Therapeutic angiogenesis involves the introduction of exogenous growth factor proteins and genes into ischemic tissues to augment endogenous factors and promote new vessel growth. Positive results from studies in animal models of peripheral arterial disease (PAD) and coronary artery disease over the past decade have supported the implementation of clinical trials testing vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) proteins and genes. Although several clinical trials reported positive results, others have been disappointing and results of a recent Phase II trial of VEGF delivered by adenovirus (the RAVE trial) were negative. It has been suggested that the duration of gene expression following delivery by adenovirus may be insufficient to produce stable vessels. Here we present direct evidence in support of this using the rabbit ischemic hindlimb model injected with adenovirus encoding VEGF165. Immunohistology indicated an activation of endothelial cell cycling and proliferation 2-3 days after VEGF delivery that coincided closely with transient VEGF expression. Ki-67-positive endothelial nuclei were evident at high levels in capillaries and large vessels in muscles from treated animals. Angiography indicated increased density of both large and small vessels in Ad-VEGF-treated muscle at 1 week, but no significant differences thereafter. The early burst of endothelial proliferation was accompanied by increased nuclear fragmentation and condensation in VEGF-treated muscles, suggesting coincident apoptosis. No further endothelial cell proliferation took place after 1 week although there was still evidence of apoptosis. The results suggest that angiogenesis is confined to the short period of VEGF expression produced by adenovirus and early gains in collateralization rapidly regress to control levels when VEGF production ceases.
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Affiliation(s)
- M J Gounis
- The Vascular Biology Institute, University of Miami School of Medicine, Miami, FL, USA
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