Stroke is a leading cause of disability and death worldwide. In this study, we identified potential therapeutic targets for stroke using a data mining, network analysis, enrichment, and docking analysis approach. We first identified 1991 genes associated with stroke from two publicly available databases: GeneCards and DisGeNET. We then constructed a protein-protein interaction (PPI) network using the STRING database and identified 1301 nodes and 5413 edges. We used Metascape to perform GO enrichment analysis and KEGG pathway enrichment analysis. The results of these analyses identified ten hub genes (TNF, IL6, ACTB, AKT1, IL1B, TP53, VEGFA, STAT3, CASP3, and CTNNB1) and five KEGG pathways (cancer, lipid and atherosclerosis, cytokine-cytokine receptor interaction, AGE RAGE signaling pathway in complications, and TNF signaling pathway) that are enriched in stroke genes. We then performed molecular docking analysis to screen potential drug candidates for these targets. The results of this analysis identified several promising drug candidates that could be used to develop new therapeutic strategies for stroke.

Small cell lung cancer (SCLC) is difficult to treat due to its aggressiveness, early metastasis, and rapid development of resistance to chemotherapeutic agents. Here, we show that treatment with a dopamine D2 receptor (D2R) agonist reduces tumour angiogenesis in multiple in vivo xenograft models of human SCLC, thereby reducing SCLC progression. An FDA-approved D2R agonist, cabergoline, also sensitized chemotherapy-resistant SCLC tumours to cisplatin and etoposide in patient-derived xenograft models of acquired chemoresistance in mice. Ex vivo, D2R agonist treatment decreased tumour angiogenesis through increased apoptosis of tumour-associated endothelial cells, creating a less favourable tumour microenvironment that limited cancer cell proliferation. In paired SCLC patient-derived specimens, D2R was expressed by tumour-associated endothelial cells obtained before treatment, but D2R was downregulated in SCLC tumours that had acquired chemoresistance. D2R agonist treatment of chemotherapy-resistant specimens restored expression of D2R. Activation of dopamine signalling is thus a new strategy for inhibiting angiogenesis in SCLC and potentially for combatting chemotherapy-refractory SCLC progression.

Platelets, traditionally regarded as passive mediators of hemostasis, are now recognized as pivotal regulators in the tumor microenvironment, establishing metabolic feedback loops with tumor and immune cells. Tumor-derived signals trigger platelet activation, which induces rapid metabolic reprogramming, particularly glycolysis, to support activation-dependent functions such as granule secretion, morphological changes, and aggregation. Beyond self-regulation, platelets influence the metabolic processes of adjacent cells. Through direct mitochondrial transfer, platelets reprogram tumor and immune cells, promoting oxidative phosphorylation. Additionally, platelet-derived cytokines, granules, and extracellular vesicles drive metabolic alterations in immune cells, fostering suppressive phenotypes that facilitate tumor progression. This review examines three critical aspects: (1) the distinctive metabolic features of platelets, particularly under tumor-induced activation; (2) the metabolic crosstalk between activated platelets and other cellular components; and (3) the therapeutic potential of targeting platelet metabolism to disrupt tumor-promoting networks. By elucidating platelet metabolism, this review highlights its essential role in tumor biology and its therapeutic implications.

Constitutive secretion of VEGF is crucial for maintaining ocular circulation while hypoxia-induced VEGF secretion plays an important role in pathological neovascularization. Previous studies have highlighted the critical function of RPE cells in these situations. The role of uveal melanocytes (UM) in VEGF production, however, has not been well described. The aim of this study was to compare VEGF production from human RPE and UM cell lines obtained in pairs from 3 donors to minimize individual variability in cellular function. Cells were subjected to hypoxia, (1% oxygen environment) or chemical hypoxia (cobalt chloride, CoCl2) at different times or dosages, respectively. The effects of these treatments on the cell viability and cell proliferation were tested using MTT and cell counting with trypan blue testing. The production of VEGF and its main upstream factor (hypoxia-inducible factors-1α, HIF-1α) were measured in the conditioned culture medium and cellular extracts, by using ELISA analysis. Additionally, mRNA levels of VEGF and HIF-1α were quantified through real-time PCR analysis. The effects of CoCl2 on the expression of VEGF and HIF-1α in UM and RPE cells were also examined using flow cytometry. Hypoxia and COCL2 exposure did not affect cell viability and cell proliferation. This study revealed that the constitutive production of VEGF by RPE cells is significantly greater than from the UM. However, UM demonstrated a more robust response to high hypoxia or chemical hypoxic stimulation compared to RPE cells. The data suggests that while RPE cells play a critical role in constitutive VEGF production under normal conditions, UM may contribute significantly to the pathological increase in VEGF under severe ocular hypoxia. The observation that intraocular injection of CoCl2 to produce local chemical hypoxia, results in a significant increase of VEGF levels in intraocular fluids and tissues, has not been reported previously. While this model cannot currently test the in vitro results, it may help further our understanding of UM and RPE cells' roles in VEGF production in future studies using more advanced technologies in a well-established in vivo model.

Vascular endothelial growth factor (VEGF) is a critical regulator of angiogenesis, playing a pivotal role in both physiological and pathological processes. It promotes the formation of new blood vessels and activates downstream signaling pathways that regulate endothelial cell function. This review highlights recent advancements in the understanding of VEGF's molecular structure and its isoforms, as well as their implications in disease progression. It also explores the mechanisms of VEGF inhibitors. While VEGF inhibitors show promise in the treatment of cancer and other diseases, their clinical use faces significant challenges, including drug resistance, side effects, and complex interactions with other signaling pathways. To address these challenges, future research should focus on: (i) enhancing the understanding of VEGF subtypes and their distinct roles in various diseases, supporting the development of personalized treatment strategies; (ii) developing combination therapies that integrate VEGF inhibitors with other targeted treatments to overcome resistance and improve efficacy; (iii) optimizing drug delivery systems to reduce off-target effects and enhance therapeutic outcomes. These approaches aim to improve the effectiveness and safety of VEGF-targeted therapies, offering new possibilities for the treatment of VEGF-related diseases.

Vascular endothelial growth factors (VEGFs) play a crucial role in regulating physiological angiogenesis and homeostasis during growth and development. Recent advancements in our knowledge of VEGFs have revealed their complex role in coordinating vascular homeostasis and pathological role in various airway allergic reactions and structural remodeling, especially in allergic asthma and allergic rhinitis (AR), which has become more apparent.

After an extensive search of PubMed and Web of Science databases, our review covered articles published from 1989 to 2024. The purpose of this review was to review previous studies on VEGFs involved in inflammatory progression and tissue remodeling in airway allergic diseases, to summarize the relevant pathways. This article further reviews that VEGFs and their receptors can also be potential targets for treating airway allergic diseases.

The prevalence of airway allergic diseases is increasing, which has caused a serious economic burden. VEGFs and their receptors have been recognized as potential targets for therapeutic interventions, which have been effectively applied in the treatment of tumors and other diseases. Fully elucidating the involvement of VEGFs in the disease process will help us understand their mechanisms of action and develop targeted therapies for allergic diseases.

Ocular neovascularization, a hallmark of several vision-threatening diseases, including retinopathy of prematurity (ROP) and wet age-related macular degeneration (wet AMD), is commonly treated with intravitreal injections of anti-VEGF agents. However, these treatments are limited by invasiveness and drug resistance, highlighting the need for alternative therapies. Sclareol (SCL), a labdane diterpenoid derived from Salvia sclarea, exhibits various biological activities, but its potential role in angiogenesis and pharmacokinetics after oral administration remain unexplored.

Hypoxia-induced endothelial cells (ECs) were used as an in vitro model, while mouse oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) were used as in vivo models. The pharmacokinetics of SCL in plasma, retina, and choroid were analyzed after oral administration in mice. Furthermore, the underlying mechanisms were elucidated through an integrative approach combining transcriptomics, metabolomics, network pharmacology, molecular docking, and molecular dynamics simulation.

SCL inhibited hypoxia-induced EC proliferation, permeability, migration, tube formation, sprouting, glycolysis, mitochondrial respiration, and oxidative stress by modulating the PI3K-AKT-FOXO1 pathway. Additionally, Oral administration of SCL significantly inhibited OIR and CNV progression in mice, demonstrating enhanced therapeutic efficacy when combined with intravitreal aflibercept (Eylea) injection.

SCL is a promising orally administered natural compound for ocular neovascularization, offering a potential alternative or adjunctive therapy to existing anti-VEGF treatments.

Although delayed wound healing is an important clinical complication in diabetic patients, few targeted treatments are available, and it remains a challenge to promote diabetic wound healing. Impaired neovascularization is one of the prime characteristics of the diabetic phenotype of delayed wound healing. Additionally, increased levels of reactive oxygen species (ROS) and chronic low-grade inflammation and hypoxia are associated with diabetes, which disrupts mechanisms of wound healing. We developed lignosulfonate composites with several wound healing properties, including sustained oxygen release through calcium peroxide nanoparticles and reactive oxygen species and free radical scavenging by thiolated lignosulfonate nanoparticles. Sustained release of oxygen and ROS-scavenging by these composites promoted endothelial cell (EC) branching and characteristic capillary-like network formation under high glucose conditions in vitro. Gene co-expression network analysis of RNA-sequencing results from ECs cultured on lignin composites showed regulation of inflammatory pathways, alongside the regulation of angiogenic hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth (VEGF) factor pathways. In vivo, lignosulfonate composite treatment promoted VEGF expression and angiogenesis in full thickness skin wounds in diabetic mice, a model of delayed wound healing. Treatment of diabetic wounds with lignosulfonate composites also promoted faster epithelial gap closure and increased granulation tissue deposition by day 7 post-wounding, with a higher presence of pro-healing type macrophages. Our findings demonstrate that lignosulfonate composites promote diabetic wound healing without requiring additional drugs. This highlights the potential of functionalized lignosulfonate for wound healing applications that require balanced antioxidation and controlled oxygen release. STATEMENT OF SIGNIFICANCE: The lignosulfonate composites developed in this study offer a promising solution for delayed wound healing in diabetic patients. By effectively addressing key factors contributing to the multifaceted pathophysiology of the diabetic wounds, including impaired neovascularization, increased ROS levels, and chronic inflammation and wound proteolysis, these composites demonstrate significant potential for promoting wound repair and reducing the complications associated with diabetic wounds. The unique combination of pro-angiogenic, oxygen-releasing, ECM remodeling and antioxidant properties in these lignosulfonate-based materials highlights their potential as a valuable therapeutic option, providing a multi-pronged approach to diabetic wound healing without the need for additional drugs.

The translation of biomedical devices and drug research is an expensive and long process with a low probability of receiving FDA approval. Developing physiologically relevant in vitro models with human cells offers a solution to not only improving the odds of FDA approval but also to expand our ability to study complex in vivo systems in a simpler fashion. Animal models remain the standard for pre-clinical testing; however, the data from animal models is an unreliable extrapolation when anticipating a human response in clinical trials, thus contributing to the low rates of translation. In this review, we focus on in vitro vascular or angiogenic models because of the incremental role that the vascular system plays in the translation of biomedical research. The first section of this review discusses the most common angiogenic cytokines that are used in vitro to initiate angiogenesis, followed by angiogenic inhibitors where both initiators and inhibitors work to maintain vascular homeostasis. Next, we evaluate previously published in vitro models, where we evaluate capturing the physical environment for biomimetic in vitro modeling. These topics provide a foundation of parameters that must be considered to improve and achieve vascular biomimicry. Finally, we summarize these topics to suggest a path forward with the goal of engineering human in vitro models that emulate the in vivo environment and provide a platform for biomedical device and drug screening that produces data to support clinical translation.

Myocardial ischemia-reperfusion injury (MI/R) is a negative and adverse cardiovascular outcome following myocardial ischemia, cardiac surgery, or circulatory arrest. Prolyl endopeptidase (PREP) appears to be involved in inflammatory responses, so it could be a possible therapeutic target for counteracting ischemia injury. This study aimed to investigate the role of PREP inhibitor, KYP-2047 (4-phenylbutanoyl-l-prolyl-2(S)-cyanopyrolidine), in the modulation of molecular and biochemical processes involved in MI/R. MI/R was induced through coronary artery occlusion (15 min), followed by reperfusion (2 h). KYP-2047 was intraperitoneally administrated at doses of 2.5 mg/kg and 5 mg/kg 24 h before the surgical procedures. The hearts were removed and processed for analysis. KYP-2047 treatment limited ischemic myocardial-induced histological damage and neutrophil accumulation, limiting inflammation, fibrosis, and apoptosis processes. Additionally, KYP-2047 was able to modulate p-38 and p-ERK expression, suggesting an improving role in recovering cardiac function. These findings highlighted the protective effects of KYP-2047 pretreatment in MI/R injury, suggesting PREP as a potential target therapy for the pathogenesis of MI/R. Although the molecular mechanisms underlying the action of KYP-2047 are still to be explored, these results suggested that the regulation of NF-κB, apoptosis, and MAPK pathways by KYP-2047 treatment could preventatively limit the damage caused by MI/R.

This was a prospective multicenter, randomized, double-masked, active-controlled study, the aim of which was to demonstrate the efficacy and safety of intravitreal ONS-5010 (bevacizumab-vikg) in eyes with neovascular age-related macular degeneration (nAMD). This was a phase III trial on ONS-5010 (NORSE TWO).

Treatment-naïve nAMD patients aged 50 years and older with a best-corrected distance visual acuity (BCVA) of 25 to 67 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and evidence of disease activity were included. Patients randomized to ONS-5010 received monthly intravitreal doses of 1.25 mg of ONS-5010, bevacizumab-vikg (Outlook Therapeutics) for 12 months. Patients randomized to ranibizumab received 0.50 mg of ranibizumab on days 0, 30, 60, 150, and 240 based on the PIER study dosing regimen.

The primary end point was the proportion of patients who gained ≥ 15 letters from baseline in BCVA at 11 months, and evaluating the safety and tolerability of intravitreal injections of ONS-5010 administered monthly from baseline to 12 months. One hundred thirteen participants were included in the ONS-5010 group and 115 participants were included in the ranibizumab group. Respectively, 41.7% and 23.1% of patients gained ≥ 15 letters (3 lines) of visual acuity, with a risk difference of 0.1859 [95% CI = 0.0442, 0.3086]; P = 0.0052. The change in BCVA from baseline to 11 months was found to be 11.2 ± 12.19 and 5.8 ± 14.80 ETDRS letters, respectively. The number of patients gaining ≥ 5 and ≥ 10 letters and patients losing < 15 letters was significantly higher in the ONS-5010 group. Similarly, patients with a Snellen visual acuity equivalent of 20/200 (35 ETDRS letters) or worse at 11 months were significantly fewer in the ONS-5010 group. Only one patient in the ONS-5010 group had a study-related serious ocular adverse event (SAE), namely, elevated intraocular pressure. The most common adverse event in the ONS-5010 group was conjunctival hemorrhage (8.8%), and reduced visual acuity in the ranibizumab group (12.2%).

In the prescribed treatment plan, ONS-5010 exhibited strong effectiveness in improving or stabilizing visual acuity and was also well tolerated. Bevacizumab and ranibizumab displayed a comparable safety profile. [Ophthalmic Surg Lasers Imaging Retina 2025;56:178-189.].

Neo-vascularization plays a key role in achieving long-term viability of engineered cells contained in medical implants used in precision medicine. Moreover, strategies to promote neo-vascularization around medical implants may also be useful to promote the healing of deep wounds. In this context, a biocompatible, electroconductive borophene-poly(ε-caprolactone) (PCL) 3D platform is developed, which is called VOLT, to support designer cells engineered with a direct-current (DC) voltage-controlled gene circuit that drives secretion of vascular endothelial growth factor A (VEGFA). The VOLT platform consists of a 3D-printed borophene-PCL honeycomb-shaped matrix decorated with borophene-PCL nanofibers by electrospinning. The honeycomb structure provides mechanical stability, while the nanofibers facilitate the adhesion, migration, and proliferation of the engineered cells. The cells incorporate a DC-powered reactive oxygen species (ROS)-sensing gene circuit wired to an engineered synthetic promoter that triggers secretion of VEGFA to promote vascularization in the adjacent extracellular matrix. Cells engineered with this gene circuit and enclosed in the VOLT matrix, termed the VOLTVEGFA system, can be simply triggered using off-the-shelf AA batteries, utilizing the established ability of a brief DC bias to generate non-cytotoxic levels of ROS. For proof-of-concept, a subcutaneous wound-healing model in rats is chosen. Electrostimulation of a VOLTVEGFA implant (5 V, 20 s per day) induced secretion of VEGFA, and significantly accelerated neovascularization and granulation tissue formation, resulting in faster wound closure compared with non-stimulated controls. Complete re-epithelialization and dermal regeneration are observed within 15 days of application.

Cervical cancer is preventable with screening and vaccination approaches; however, access to these preventative measures is limited both nationally and globally and thus many women will still develop cervical cancer. Novel treatments and practice-changing research have improved cervical cancer outcomes over the past few decades. In this Review, we discuss clinical trials that have refined or redefined the treatment of cervical cancers across the early stage, locally advanced, persistent, recurrent and/or metastatic disease settings. Advances for patients with early stage disease have been achieved through trials evaluating less extensive and fertility-preserving surgeries, different surgical approaches (open versus minimally invasive), and sentinel versus full pelvic lymph node dissection. We also discuss results from trials testing the use of neoadjuvant, induction and adjuvant chemotherapy as well as immune-checkpoint inhibitors in patients with locally advanced disease. Finally, we review the progress made with systemic chemotherapy and novel therapeutics, including anti-angiogenic agents, immune-checkpoint inhibitors and antibody-drug conjugates, in the setting of metastatic and/or recurrent cervical cancer. The advances highlighted in this manuscript have reduced morbidity and improved overall survival for patients with this challenging-to-treat disease, while also inspiring additional research and trials in the field.

Chronic wound healing often encounters challenges characterized by prolonged inflammation and impaired angiogenesis. While the immune response plays a pivotal role in orchestrating the intricate process of wound healing, excessive inflammation can hinder tissue repair. In this study, a bilayer alginate hydrogel system encapsulating polyelectrolyte complex nanoparticles (PCNs) loaded with anti-inflammatory cytokines and angiogenic growth factors is developed to address the challenges of chronic wound healing. The alginate hydrogel is designed using two distinct crosslinking methods to achieve differential degradation, thereby enabling precise spatial and temporal controlled release of PCNs. Initially, interleukin-10 (IL-10) is released to mitigate inflammation, while unsaturated PCNs bind and remove accumulated pro-inflammatory cytokines at the wound site. Subsequently, angiogenic growth factors, including vascular endothelial growth factor and platelet-derived growth factor, are released to promote vascularization and vessel maturation. Our results demonstrate that the bilayer hydrogel exhibits distinct degradation kinetics between the two layers, facilitating the staged release of multiple signaling molecules. In vitro experiments reveal that IL-10 can activate the Jak1/STAT3 pathway, thereby suppressing pro-inflammatory cytokines and chemokines while down-regulating inflammation-related genes. In vivo studies demonstrate that application of the hydrogel in chronic wounds using diabetic murine model promotes healing by positively modulating multiple integral reparative mechanisms. These include reducing inflammation, promoting macrophage polarization towards a pro-regenerative phenotype, enhancing keratinocyte migration, stimulating angiogenesis, and expediting wound closure. In conclusion, our hydrogel system effectively mitigates inflammatory responses and provides essential physiological cues by inducing a synergistic angiogenic effect, thus offering a promising approach for the treatment of chronic wounds.

Cellular phenotypic transformation is a key process that occurs during the development and progression of atherosclerosis. Within the arterial wall, endothelial cells, vascular smooth muscle cells, and macrophages undergo phenotypic changes that contribute to the pathogenesis of atherosclerosis. miRNAs have emerged as potential biomarkers for cellular phenotypic changes during atherosclerosis. Monitoring miR-155-5p, miR-210-3p, and miR-126-3p or 5p levels could provide valuable insights into disease progression, risk of complications, and response to therapeutic interventions. Moreover, miR-92a-3p's elevated levels in atherosclerotic plaques present opportunities for predicting disease progression and related complications. Baseline levels of miR-33a/b hold the potential for predicting responses to cholesterol-lowering therapies, such as statins, and the likelihood of dyslipidemia-related complications. Additionally, the assessment of miR-122-5p levels may offer insights into the efficacy of low-density-lipoprotein-lowering therapies. Understanding the specific miRNA-mediated regulatory mechanisms involved in cellular phenotypic transformations can provide valuable insights into the pathogenesis of atherosclerosis and potentially identify novel therapeutic targets.

As a gatekeeper of the airway epithelial cells, E-cadherin is not only a critical component for the maintenance of epithelial integrity, but also engaged in pathological processes through the release of a soluble form (sE-cadherin). This study was aimed to investigate the role of sE-cadherin in ALI/ARDS. Serum samples from patients with ARDS and healthy volunteers were collected for the detection of sE-cadherin. An LPS-induced mouse model was induced to analyze the expression of sE-cadherin, and a neutralizing antibody against sE-cadherin (DECMA-1) was given to the LPS-exposed mice. The effects of recombinant sE-cadherin were tested both in vitro and in vivo, and VEGFR2 inhibition was used to explore a possible mechanism for sE-cadherin-induced pulmonary inflammation. We observed an increased level of sE-cadherin in ARDS patients as well as in LPS-exposed mice. In vivo treatment of DECMA-1 significantly attenuated LPS-induced inflammation. In vitro, exogenous sE-cadherin can dramatically upregulate the expression of VEGF in THP1-derived macrophages and human primary macrophages. In addition, intratracheal instillation of recombinant sE-cadherin leads to significant increased infiltration of neutrophils as well as overproduction of IL-6 and IL1β, which could be attenuated by inhibition of VEGF/VEGFR2 signaling. While blockade of the VEGF/VEGFR2 pathway inhibited pulmonary inflammatory responses in LPS-exposed mice. Taken together, our data demonstrated that sE-cadherin contributes to lung inflammation in ALI/ARDS, which is related to activation of the VEGF/VEGFR2 pathway.

Age-related macular degeneration (AMD) is one of the most common neuroinflammatory diseases that is the leading cause of blindness worldwide. AMD is caused by not only mutations in immune-related genes such as Cfh (complement factor H) but also the accumulation of environmental factors such as obesity and other inflammatory triggers with age. Our study found that the past histories of obesity can lead to immunological reprogramming in the innate immune system and affect the development of AMD in later life. This reveals a new link in the role of innate immune memory in neuroinflammatory diseases such as AMD, and intervention in innate immune memory may be a new therapeutic strategy.

Translationally controlled tumor protein (TCTP) is a regulatory protein that plays pivotal roles in cellular processes including the cell cycle, apoptosis, microtubule stabilization, embryo development, stress responses, and cancer. However, the molecular mechanism by which it promotes tumor angiogenesis is still unclear. In this study, we explored the mechanisms underlying stimulation of angiogenesis by a novel TCTP. Recombinant TCTP enhanced vascular endothelial growth factor (VEGF)-induced endothelial cell migration, capillary-like tubular structure formation, and cell proliferation by interacting with VEGF receptor 2 (VEGFR-2) in vitro. In contrast, we showed that TCTP knockdown (using short interfering [si]TCTP) led to a decrease in ovarian tumor cells. We also examined the expression of VEGF and hypoxia inducible factor 1 (HIF-1α), an important angiogenic factor. The expression of VEGF as well as HIF-1α was dramatically decreased by siTCTP. Mechanistically, siTCTP inhibited VEGFR-2 tyrosine phosphorylation and phosphorylation of its downstream targets PI3K, Akt, and mTOR. Collectively, these findings indicate that TCTP can promote proliferation and angiogenesis via the VEGFR-2/PI3K and mTOR signaling pathways in ovarian tumor cells, providing new insight into the mechanism behind the involvement of TCTP in tumor angiogenesis.

The endothelial glycocalyx, lining the apical surface of the endothelium, is involved in a host of vascular processes. The glycocalyx is comprised of a network of membrane-bound proteoglycans and glycoproteins along with associated plasma proteins. One such glycoprotein is endomucin (EMCN), which our lab has revealed is a modulator of VEGFR2 function. Intravitreal injection of siEMCN into the eyes of P5 mice impairs vascular development. In vitro silencing of EMCN suppresses VEGF-induced proliferation and migration. Signaling pathways that drive cell migration converge on cytoskeletal remodeling. By coupling co-immunoprecipitation with liquid chromatography/mass spectrometry, we identified interactions between EMCN and proteins associated with actin cytoskeleton organization. The aim of the study was to investigate the influence of EMCN on cytoskeleton dynamics in angiogenesis. EMCN depletion resulted in reduction of F-actin levels, whereas overexpression of EMCN induced increased membrane protrusions in cells that were rich in stress fibers. The reorganization of the actin filaments did not depend on VEGFR2 signaling, suggesting that EMCN connects the cytoskeleton and the glycocalyx.

The discovery of antivascular endothelial growth factor medications has resulted in a substantial change in diabetic retinopathy treatment. The most common cause of diabetic retinopathy blindness is Diabetic Macular Edema. The pathophysiology of Diabetic Macular Edema is thought to include the well-known pro-angiogenic and pro-permeability factor vascular endothelial growth factor. Over the past decade, drugs that impede the functions of vascular endothelial growth factors have established themselves as a standard-of-care treatment for a range of ocular ailments and improved patients' clinical results with diabetic retinopathy and Diabetic Macular Edema, and their frequency has grown exponentially with the introduction of these agents Pegaptanib, Ranibizumab, and Aflibercept which are approved for ophthalmic indications, while Bevacizumab is used off-label. These medications delivered intravitreally have halted the vascular development of diabetic retinopathy. Various randomized trials have proven that antivascular endothelial growth factor medication is safe and effective in preserving vision. Following an extensive period of preclinical development aimed at enhancing and defining its biological impacts, these drugs were shown in clinical trials to be effective in treating diabetic retinopathy and other ophthalmic conditions. Data from various sources suggest that Pegaptanib, Ranibizumab, and Aflibercept are costly, while Bevacizumab is cost-effective, and in low and middle-income nations, it is thus a desirable therapy choice. However, issues with compounding, counterfeiting, and off-label usage restrict its availability in many nations. The pharmacology, pharmacokinetics, pharmacodynamics, adverse effects, and contraindications of antivascular endothelial growth factor agents are discussed, and the results of clinical trials evaluating their efficacy are summarized.

As a new alternative to antibody-drug conjugates, we developed "ligand-targeting" peptide-drug conjugates (PDCs), in which conformationally constrained helix-loop-helix (HLH) peptide M49 targeting human vascular endothelial growth factor-A (VEGF) was used as a drug carrier. The biochemical study showed that HLH peptide M49 made a complex with VEGF in the extracellular environment, and then the M49/VEGF complex interacts with the receptor on the cell surface to induce cellular internalization via the endocytic pathway. Here, we present an X-ray crystal structure of the M49/VEGF complex at 1.5 Å resolution using a protein crystal grown in microgravity. The structure illustrated the "ligand-targeting" cellular uptake mechanism for intracellular drug delivery and the molecular basis on the peptide-VEGF binding mode with tight binding and high target specificity. In addition, mutational studies and thermodynamic analysis provided information on the driving forces of the complex formation. This work would contribute to the design of mid-size molecular-targeting peptides as well as HLH peptides, advancing the research in drug discovery and chemical biology.

Indirect revascularization is one of the main techniques for the treatment of Moyamoya disease. The formation of good collateral circulation is a key measure to improve cerebral blood perfusion and reduce the risk of secondary stroke, and is the main method for evaluating the effect of indirect revascularization. Therefore, how to predict and promote the formation of collateral circulation before and after surgery is important for improving the success rate of indirect revascularization in Moyamoya disease. Previous studies have shown that vascular endothelial growth factor, endothelial progenitor cells, Caveolin-1, and other factors observed in patients with Moyamoya disease may play a key role in the generation of collateral vessels after indirect revascularization through endothelial hyperplasia and smooth muscle migration. In addition, mutations in the genetic factor RNF213 have also been associated with this process. This study summarizes the factors and mechanisms influencing collateral circulation formation after indirect revascularization in Moyamoya disease.

Mid-sized binding peptides have recently emerged as a new therapeutic modality. A helix-loop-helix (HLH) peptide was designed as a scaffold for combinatorial peptide libraries. We screened the HLH peptide libraries against human vascular endothelial growth factor-A (VEGF) to generate a peptide, VS42-LR3, which inhibited VEGF/receptor interaction and suppressed tumor growth in a murine xenograft model of human colorectal cancer. Here, we report the first crystal structure of the HLH peptide in a complex with VEGF at high resolution using space-grown protein crystals. The X-ray structural analysis revealed that the monomeric VS42-LR3 adopted an HLH structure and bound to VEGF at the VEGF receptor-binding site. Interestingly, from the site-directed mutagenesis, thermodynamic analysis, and molecular dynamic simulations, it turned out that the loop region in the non-interacting surface to VEGF affected the structural rigidity of the whole HLH to increase the binding affinity. These findings provide valuable insights for the design of more structurally stable and higher affinity mid-sized binding peptides as well as HLH peptides, that could play a crucial role in advancing molecular-targeting therapies.

Many types of viruses directly or indirectly target the vascular endothelial growth factor (VEGF) system, which is a central regulator of vasculogenesis and angiogenesis in physiological homeostasis, causing diverse pathologies. Other viruses have been developed into effective therapeutic tools for VEGF modulation in conditions such as cancer and eye diseases. Some viruses may alter the levels of VEGF in the pathogenesis of respiratory syndromes, or they may encode VEGF-like factors, promoting vascular disruption and angiogenesis to enable viruses' systemic spread. Oncogenic viruses may express interactive factors that perturb VEGF's functional levels or downstream signaling, which increases the neovascularization and metastasis of tumors. Furthermore, many viruses are being developed as therapeutic vectors for vascular pathologies in clinical trials. Major examples are those viral vectors that inhibit the role of VEGF in the neovascularization required for cancer progression; this is achieved through the induction of immune responses, by exposing specific peptides that block signaling or by expressing anti-VEGF and anti-VEGF receptor-neutralizing antibodies. Other viruses have been engineered into effective pro- or anti-angiogenesis multitarget vectors for neovascular eye diseases, paving the way for therapies with improved safety and minimal side effects. This article critically reviews the large body of literature on these issues, highlighting those contributions that describe the molecular mechanisms, thus expanding our understanding of the VEGF-virus interactions in disease and therapy. This could facilitate the clinical use of therapeutic virus vectors in precision medicine for the VEGF system.

The present study aims to identify genomic variants through a whole genome sequencing (WGS) approach and uncover biological pathways associated with adaptation and fitness in Indian yak populations. A total of 30 samples (10 from each population) were included from Arunachali, Himachali and Ladakhi yak populations. WGS analysis revealed a total of 32171644, 27260825, and 32632460 SNPs and 4865254, 4429941, and 4847513 Indels in the Arunachali, Himachali, and Ladakhi yaks, respectively. Genes such as RYR2, SYNE2, BOLA, HF1, and the novel transcript ENSBGRG00000011079 were found to have the maximum number of high impact variants in all three yak populations, and might play a major role in local adaptation. Functional enrichment analysis of genes harboring high impact SNPs revealed overrepresented pathways related to response to stress, immune system regulation, and high-altitude adaptation. This study provides comprehensive information about genomic variants and their annotation in Indian yak populations, thus would serve as a data resource for researchers working on the yaks. Furthermore, it could be well exploited for better yak conservation strategies by estimating population genetics parameters viz., effective population size, inbreeding, and observed and expected heterozygosity.

Fine-tuning angiogenesis, the development of new blood vessels, is essential for maintaining a healthy circulatory and lymphatic system. The small glycoprotein vascular endothelial growth factors (VEGF) are the key mediators in this process, binding to their corresponding membrane-bound VEGF receptors (VEGFRs) to activate angiogenesis signaling pathways. These pathways are crucial throughout human life as they are involved in lymphatic and vascular endothelial cell permeability, migration, proliferation, and survival. Neovascularization, the formation of abnormal blood vessels, occurs when there is a dysregulation of angiogenesis and can result in debilitating disease. Hence, VEGFRs have been widely studied to understand their role in disease-causing angiogenesis. VEGFR1, also known as Fms-like tyrosine kinase-1 (FLT-1), is also found in a soluble form, soluble FLT-1 or sFLT-1, which is known to act as a VEGF neutralizer. It is incorporated into anti-VEGF therapy, designed to treat diseases caused by neovascularization. Here we review the journey of sFLT-1 discovery and delve into the alternative splicing mechanism that creates the soluble receptor, its prevalence in disease states, and its use in current and future potential therapies.

Active smokers are known to be at an increased risk of both gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD), however the role of passive smoking remains unclear. In this study, we aimed to examine whether secondhand smoke (SHS) is associated with PUD and GERD.

In this population-based study, we conducted a large-scale analysis with 88,297 never-smokers (male: 18,595; female: 69,702; mean age 50.1 ± 11.0 years) from the Taiwan Biobank. The exposure group was comprised of those who had been exposed to SHS, and the no exposure group as those without SHS exposure. According to the frequency of exposure, we further divided the participants into "no exposure," "<1 h per week," and "≥1 h per week" groups. A cutoff point of 1 h per week was chosen according to the median exposure time in our participants. Associations between SHS and SHS frequency with PUD and GERD were assessed.

Of the 88,297 enrolled participants, 11,909 (13.5%) had PUD and 76,388 (86.5%) did not. In addition, 11,758 (13.3%) had GERD and 76,539 (86.7%) did not. Multivariable analysis showed a significant association between SHS with PUD (odds ratio [OR] = 1.166; 95% confidence interval [CI] = 1.084-1.254; p < 0.001), and GERD (OR = 1.131; 95% CI = 1.053-1.216; p = 0.001). Furthermore, those exposed to SHS ≥ 1 h per week (vs. no exposure) were associated with higher risks of PUD (OR = 1.232; 95% CI = 1.121-1.355; p < 0.001) and GERD (OR = 1.200; 95% CI = 1.093-1.319; p < 0.001).

SHS was significantly associated with PUD and GERD. Furthermore, exposure to SHS ≥ 1 h per week (vs. no exposure) was associated with a 1.23-fold higher risk of PUD and 1.20-fold higher risk of GERD. This study represents the largest population-based investigation to explore the association between SHS with PUD and GERD in Taiwanese never-smokers.

Gastric cancer (GC) is a globally frequent cancer, in particular leading in mortality caused by digestive tract cancers in China. Vascular endothelial growth factor A (VEGFA) is excessively expressed in cancers including GC; its involvement in GC development, particularly in multidrug resistance (MDR), and the signal route it affects in GC remain unknown. To explore the roles VEGFA plays during progression and MDR formation in GC, we studied its function in a VEGFA-deleted GC cell platform.

We initially assessed the importance of VEGFA in GC and MDR using database analysis. Then, using CCK8, wound healing, transwell, scanning electron microscopy, immunofluorescence, flow cytometry, and other techniques, the alterations in tumor malignancy-connected cell behaviors and microstructures were photographed and evaluated in a VEGFA-gene-deleted GC cell line (VEGFA-/-SGC7901). Finally, the mechanism of VEGFA in GC progression and MDR was examined by Western blot.

Database analysis revealed a strong correlation between high VEGFA expression and a poor prognosis for GC. The results showed that VEGFA deletion reduced GC cell proliferation and motility and altered microstructures important for motility, such as the depolymerized cytoskeleton. VEGFA deletion inhibited the growth of pseudopodia/filopodia and suppressed the epithelial-mesenchymal transition (EMT). The occurrence of MDR is induced by overactivation of the MAPK-AKT and TGFβ signaling pathways, while PTEN inhibits these pathways.

All findings suggested that VEGFA acts as a cancer enhancer and MDR inducer in GC via the MAPK-AKT/PTEN/TGFβ signal pathway.

Oral cancers, which include tumors of the oral cavity, salivary glands, and pharynx, are becoming increasingly prevalent worldwide. Squamous cell carcinoma accounts for over 90% of malignant oral lesions, with oral squamous cell carcinoma (OSCC) being notably common in the Indian subcontinent and other regions of Asia. This is especially true in South-Central Asia, including Sri Lanka, where it is particularly prevalent among men. This study aims to evaluate the levels of Vascular Endothelial Growth Factor-A (VEGF-A) and Cytokeratin-19 (CK-19) mRNAs in whole blood as a potential method for the early detection of OSCC.

The study included 40 patients (each from OSCC, Oral Submucous Fibrosis (OSF), Oral Leukoplakia (OLK), Oral Lichen Planus (OLP), and 10 healthy controls. The expression levels of VEGF-A and CK-19 mRNAs were measured from extracellular RNA extracted from whole blood samples using real-time reverse transcription polymerase chain reaction (RT-PCR) with sequence-specific primers. Receiver operating characteristic (ROC) curve analysis was used to evaluate the effectiveness of these biomarkers in detecting OSCC.

The results demonstrated a significant increase in blood transcripts of the candidate mRNAs CK-19 and VEGF-A in patients with OSCC, OSF, OLK, and OLP. The Wilcoxon signed-rank test revealed a p-value of 0.002 for each specific comparison between diseased patients and healthy controls (i.e., OSCC vs. HC, OSF vs. HC, OLP vs. HC, OLK vs. HC) for both CK-19 and VEGF-A. When these two biomarkers were used together, they provided a 60% predictive probability for patients with OSCC (p = 0.023).

This study highlights the efficacy of blood mRNA transcriptome diagnostics in detecting OSCC. This innovative clinical approach has the potential to be a robust, efficient, and reliable tool for early cancer detection. Blood-based transcriptomes could be further explored for their effectiveness in various health contexts and for routine health monitoring.

Anti-angiogenic drugs (AADs), which mainly target the vascular endothelial growth factor-A signaling pathway, have become a therapeutic option for cancer patients for two decades. During this period, tremendous clinical experience of anti-angiogenic therapy has been acquired, new AADs have been developed, and the clinical indications for AAD treatment of various cancers have been expanded using monotherapy and combination therapy. However, improvements in the therapeutic outcomes of clinically available AADs and the development of more effective next-generation AADs are still urgently required. This review aims to provide historical and perspective views on tumor angiogenesis to allow readers to gain mechanistic insights and learn new therapeutic development. We revisit the history of concept initiation and AAD discovery, and summarize the up-to-date clinical translation of anti-angiogenic cancer therapy in this field.

Osteoporotic bone defects are serious medical problems due to their sparse bone structure, difficulty in restoration and reconstruction, and high recurrence rates, which also result in heavy economic and social burdens. Herein, we developed a hierarchical hydrogel composed of alendronate sodium (AS)/Mg2+-loaded inverse opal methylpropenylated gelatin (GelMA) hydrogel microspheres (IOHM-AS-Mgs) within methylpropenylated poly(hyaluronic acid) (HAMA) for osteoporotic bone defect treatment. The IOHM-AS-Mgs displayed good cytocompatibility and cell adhesion and strongly stimulated osteogenesis at the transcriptomic and protein levels. When this treatment was applied to the osteoporotic bone defect area, HAMA was used to fix the microspheres. The results of the microcomputed tomography (micro-CT) and histological analyses indicated that the hierarchical hydrogel had the best therapeutic effect. Therefore, this hydrogel is a new candidate for osteoporotic bone defect treatment.

Accumulating evidence suggests a link between vascular endothelial growth factor (VEGF), erectile dysfunction (ED), and metabolic syndrome (Mets), possibly because VEGF can alter the physiological pathways involved in the regulation of endothelial cell proliferation. This study aimed to investigate the genetic susceptibility of VEGF 2578C>A polymorphism to the development of ED and Mets. Collected data included five-item International Index of Erectile Function (IIEF-5), components of Mets, and VEGF 2578C>A polymorphism. A total of 596 subjects from Kaohsiung with a mean age of 55.5 years were enrolled, data collection was done at our hospital. Individuals carrying the VEGF 2578 A allele (CA+AA genotypes) demonstrated a higher prevalence of ED compared to those with the CC genotype, with an adjusted odds ratio (OR) of 1.582 (95% confidence interval [95% CI] = 1.123-2.227, p value = 0.009) in multivariate binary regression analysis. Similarly, individuals carrying the VEGF 2578 A allele showed a higher prevalence of Mets compared to those with the CC genotype, with an adjusted OR of 2.461 (95% CI = 1.491-4.064, p value < 0.001). Furthermore, A allele carriers had significantly lower IIEF-5 scores and a higher number of Mets components compared to those with the C allele (P value < 0.001, respectively). In conclusion, VEGF 2578 A allele carriers are at a greater risk of both Mets and ED, suggesting that the VEGF 2578C>A polymorphism may serve as a common genetic susceptibility factor in the development of both disorders. Further research is warranted to evaluate the mechanisms underlying this association.

Due to its anti-angiogenic properties, trebananib is frequently employed in the treatment of cancer patients, particularly those with ovarian cancer. We conducted a meta-analysis to assess the efficacy and safety profile of trebananib in combination with other drugs for treating both ovarian and non-ovarian cancer patients.

Our search encompassed PubMed, Medline, Cochrane, and Embase databases, with a focus on evaluating study quality. Data extraction was conducted from randomized controlled trials (RCTs), and RevMan 5.3 facilitated result analysis.

Combining trebananib with other drugs extended progression-free survival (PFS) [HR 0.81, (95%CI: 0.65, 0.99), p = 0.04] and overall survival (OS) [HR 0.88, (95%CI: 0.79, 1.00), p = 0.04] in ovarian cancer patients. Ovarian cancer patients exhibited a higher objective response rate (ORR) with trebananib compared to non-ovarian cancer cohorts. Moreover, the incorporation of trebananib into the standard treatment regimen for malignant tumors did not significantly elevate drug-related adverse events [RR 1.05, (95% CI: 1.00, 1.11), p = 0.05].

Trebananib plus other drugs can improve the PFS, OS and ORR in patients with cancer, especially ovarian cancer. Our recommendation is to use trebananib plus other drugs to treat advanced cancer, and to continuously monitor and manage drug-related adverse events.

PROSPERO (No. CRD42023466988).

Ischemia/reperfusion injury (IRI) is a key determining agent in the pathophysiology of clinical organ dysfunction. It is characterized by an aseptic local inflammatory reaction due to a decrease in blood supply, hence deprivation of dependent oxygen and nutrients. In instances of liver transplantation, this injury may have irreversible implications, resulting in eventual organ rejection. The deterioration associated with IRI is affected by the hepatic health status and various factors such as alterations in metabolism, oxidative stress, and pro-inflammatory cytokines. The primary cause of inflammation is the initial immune response of pro-inflammatory cytokines, while Kupffer cells (KFCs) and neutrophil-produced chemokines also play a significant role. Upon reperfusion, the activation of inflammatory responses can elicit further cellular damage and organ dysfunction. This review discusses the interplay between chemokines, pro-inflammatory cytokines, and other inflammatory mediators that contribute to the damage to hepatocytes and liver failure in rats following IR. Furthermore, it delves into the impact of anti-inflammatory therapies in safeguarding against liver failure and hepatocellular damage in rats following IR. This review investigates the correlation between cytokine factors and liver dysfunction via examining databases, such as PubMed, Google Scholar, Science Direct, Egyptian Knowledge Bank (EKB), and Research Gate.

Hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu disease) affects 1 in 5000 persons, making it the second most common inherited bleeding disorder worldwide. Telangiectatic bleeding, primarily causing recurrent epistaxis and chronic gastrointestinal bleeding, is the most common and most important manifestation of this multisystem vascular disorder. HHT-associated bleeding results in substantial psychosocial morbidity and iron deficiency anemia that may be severe. Although there remain no regulatory agency-approved therapies for HHT, multiple large studies, including randomized controlled trials, have demonstrated the safety and efficacy of antifibrinolytics for mild-to-moderate bleeding manifestations and systemic antiangiogenic drugs including pomalidomide and bevacizumab for moderate-to-severe bleeding. This has led to a recent paradigm shift away from repetitive temporizing procedural management toward effective systemic medical therapeutics to treat bleeding in HHT. In this article, 4 patient cases are used to illustrate the most common and most challenging presentations of HHT-associated bleeding that hematologists are likely to encounter in daily practice. Built on a framework of published data and supported by extensive clinical experience, guidance is given for modern evidence-based approaches to antifibrinolytic therapy, antiangiogenic therapy, and iron deficiency anemia management across the HHT disease severity spectrum.

Mesenchymal stromal cells (MSCs) are investigated as cellular therapeutics for inflammatory bowel diseases and associated perianal fistula, although consistent efficacy remains a concern. Determining host factors that modulate MSCs' potency including their secretion of angiogenic and wound-healing factors, immunosuppression, and anti-inflammatory properties are important determinants of their functionality. We investigated the mechanisms that regulate the secretion of angiogenic and wound-healing factors and immune suppression of human bone marrow MSCs. Secretory analysis of MSCs focusing on 18 angiogenic and wound-healing secretory molecules identified the most abundancy of vascular endothelial growth factor A (VEGF-A). MSC viability and secretion of other angiogenic factors are not dependent on VEGF-A secretion which exclude the autocrine role of VEGF-A on MSC's fitness. However, the combination of inflammatory cytokines IFNγ and TNFα reduces MSC's VEGF-A secretion. To identify the effect of intestinal microvasculature on MSCs' potency, coculture analysis was performed between human large intestine microvascular endothelial cells (HLMVECs) and human bone marrow-derived MSCs. HLMVECs do not attenuate MSCs' viability despite blocking their VEGF-A secretion. In addition, HLMVECs neither attenuate MSC's IFNγ mediated upregulation of immunosuppressive enzyme indoleamine 2,3-dioxygenase nor abrogate suppression of T-cell proliferation despite the attenuation of VEGF-A secretion. We found that HLMVECs express copious amounts of endothelial nitric oxide synthase and mechanistic analysis showed that pharmacological blocking reverses HLMVEC-mediated attenuation of MSC's VEGF-A secretion. Together these results suggest that secretion of VEGF-A and immunosuppression are separable functions of MSCs which are regulated by distinct mechanisms in the host.

Sirolimus (SR) is a macrolide with antifungal and antitumor immunosuppressant properties, classified as a selective inhibitor of mammalian target of rapamycin (mTOR). In this study, an ionic in situ gel of SR (SR-SUS-ISG) was formulated using gellan gum, exhibiting stability regardless of temperature and pH variations, causing minimal irritation. Harnessing the physiological conditions of the eye, SR-SUS-ISG underwent gelation upon contact with ions, increasing drug viscosity and prolonging retention on the ocular surface. Concurrently, SR-SUS-ISG displayed favorable shear dilution properties, reducing viscosity at ambient temperature, enhancing fluidity, and facilitating convenient packaging and transport. Biocompatibility assessments on both human corneal epithelial cells and rabbit eyes demonstrated that SR-SUS-ISG could well be tolerated. Pharmacokinetic investigations in rabbit ocular aqueous humor revealed sustained release, improved corneal penetration, and enhanced bioavailability. Additionally, in a rat corneal alkali burn model, SR-SUS-ISG exhibited inhibitory effects on corneal neovascularization, associated with decreased levels of the inflammatory factors VEGF and MMPs. These findings suggested that SR-SUS-ISG held promise as an effective ocular drug delivery system.

Insulin-like Growth Factor-Binding Protein 7 (IGFBP7) is an extracellular matrix (ECM) glycoprotein, highly enriched in activated vasculature during development, physiological and pathological tissue remodeling. Despite decades of research, its role in tissue (re-)vascularization is highly ambiguous, exhibiting pro- and anti-angiogenic properties in different tissue remodeling states. IGFBP7 has multiple binding partners, including structural ECM components, cytokines, chemokines, as well as several receptors. Based on current evidence, it is suggested that IGFBP7's bioactivity is strongly dependent on the microenvironment it is embedded in. Current studies indicate that during physiological angiogenesis, IGFBP7 promotes endothelial cell attachment, luminogenesis, vessel stabilization and maturation. Its effects on other stages of angiogenesis and vessel function remain to be determined. IGFBP7 also modulates the pro-angiogenic properties of other signaling factors, such as VEGF-A and IGF, and potentially acts as a growth factor reservoir, while its actual effects on the factors' signaling may depend on the environment IGFBP7 is embedded in. Besides (re-)vascularization, IGFBP7 clearly promotes progenitor and stem cell commitment and may exhibit anti-inflammatory and anti-fibrotic properties. Nonetheless, its role in inflammation, immunomodulation, fibrosis and cellular senescence is again likely to be context-dependent. Future studies are required to shed more light on the intricate functioning of IGFBP7.

Exposure to microgravity during spaceflight induces the alterations in endothelial cell function associated with post-flight cardiovascular deconditioning. PIEZO1 is a major mechanosensitive ion channel that regulates endothelial cell function. In this study, we used a two-dimensional clinostat to investigate the expression of PIEZO1 and its regulatory mechanism on human umbilical vein endothelial cells (HUVECs) under simulated microgravity. Utilizing quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis, we observed that PIEZO1 expression was significantly increased in response to simulated microgravity. Moreover, we found microgravity promoted endothelial cells migration by increasing expression of PIEZO1. Proteomics analysis highlighted the importance of C-X-C chemokine receptor type 4(CXCR4) as a main target molecule of PIEZO1 in HUVECs. CXCR4 protein level was increased with simulated microgravity and decreased with PIEZO1 knock down. The mechanistic study showed that PIEZO1 enhances CXCR4 expression via Ca2+ influx. In addition, CXCR4 could promote endothelial cell migration under simulated microgravity. Taken together, these results suggest that the upregulation of PIEZO1 in response to simulated microgravity regulates endothelial cell migration due to enhancing CXCR4 expression via Ca2+ influx.