1. Targeting VEGFR1 on endothelial progenitors modulates their differentiation potential.
- Author
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d'Audigier C, Gautier B, Yon A, Alili JM, Guérin CL, Evrard SM, Godier A, Haviari S, Reille-Serroussi M, Huguenot F, Dizier B, Inguimbert N, Borgel D, Bièche I, Boisson-Vidal C, Roncal C, Carmeliet P, Vidal M, Gaussem P, and Smadja DM
- Subjects
- Animals, Cardiac Surgical Procedures, Cell Migration Assays, Cell Proliferation drug effects, Collagen metabolism, Colony-Forming Units Assay, Coronary Artery Disease blood, Coronary Artery Disease pathology, Drug Combinations, Endothelial Cells drug effects, Hindlimb blood supply, Hindlimb pathology, Humans, Ischemia pathology, Laminin metabolism, Membrane Proteins blood, Mice, Inbred C57BL, Neovascularization, Physiologic drug effects, Phosphorylation drug effects, Proteoglycans metabolism, RNA, Small Interfering metabolism, Recombinant Proteins pharmacology, Stem Cells drug effects, Vascular Endothelial Growth Factor A blood, Cell Differentiation drug effects, Endothelial Cells metabolism, Stem Cells metabolism, Vascular Endothelial Growth Factor Receptor-1 metabolism
- Abstract
Objectives: We studied whether plasma levels of angiogenic factors VEGF and placental growth factor (PlGF) in coronary artery disease patients or undergoing cardiac surgery are modified, and whether those factors modulate endothelial progenitor's angiogenic potential., Methods and Results: A total of 143 patients' plasmas from two different studies were analyzed (30 coronary artery disease patients, 30 patients with stable angina, coupled with 30 age and sex-matched controls; 53 patients underwent cardiac surgery). Among factors screened, only PlGF was found significantly increased in these pathological populations. PlGF-1 and PlGF-2 were then tested on human endothelial-colony-forming cells (ECFCs). We found that PlGF-1 and PlGF-2 induce VEGFR1 phosphorylation and potentiate ECFCs tubulogenesis in vitro. ECFCs VEGFR1 was further inhibited using a specific small interfering RNA (siRNA) and the chemical compound 4321. We then observed that the VEGFR1-siRNA and the compound 4321 decrease ECFCs tubulogenesis potential in vitro. Finally, we tested the compound 4321 in the preclinical Matrigel(®)-plug model with C57Bl/6J mice as well as in the murine hindlimb ischemia model. We found that 4321 inhibited the plug vascularization, attested by the hemoglobin content and the VE-Cadherin expression level and that 4321 inhibited the post-ischemic revascularization., Conclusion: PlGF plasma levels were found increased in cardiovascular patients. Disrupting PlGF/VEGFR1 pathway could modulate ECFC-induced tubulogenesis, the cell type responsible for newly formed vessels in vivo.
- Published
- 2014
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