title: Systemic administration of thrombin peptide TP508 enhances VEGF-stimulated angiogenesis and attenuates effects of chronic hypoxia.
abstract: Revascularization of chronic wounds and ischemic tissue is attenuated by endothelial dysfunction and the inability of angiogenic factors to stimulate angiogenesis. We recently showed that TP508, a nonproteolytic thrombin peptide, increases perfusion and NO-dependent vasodilation in hearts with chronic ischemia and stimulates NO production by endothelial cells. In this study, we investigated systemic in vivo effects of TP508 on VEGF-stimulated angiogenesis in vitro using aortic explants in normoxic and hypoxic conditions. Mice were injected with saline or TP508 and 24 h later aortas were removed and cultured to quantify endothelial sprouting. TP508 injection increased endothelial sprouting and potentiated the in vitro response to VEGF. Exposure of control explants to hypoxia inhibited basal and VEGF-stimulated endothelial cell sprouting. This effect of hypoxia was significantly prevented by TP508 injection. Thus, TP508 systemic administration increases responsiveness of aortic endothelial cells to VEGF and diminishes the effect of chronic hypoxia on endothelial cell sprouting. Studies using human endothelial cells in culture suggest that protective effects of TP508 during hypoxia may involve stimulation of endothelial cell NO production. These data suggest potential clinical benefit of using a combination of systemic TP508 and local VEGF as a therapy for revascularization of ischemic tissue.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555-0645, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Olszewska-Pazdrak
authors.forename: Darrell H
authors.initials: DH
authors.lastname: Carney
mesh_terms: D000595:Amino Acid Sequence; D043925:Angiogenesis Inducing Agents; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000502:physiology; D015687:Cell Hypoxia / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000737:chemistry; D013917:Thrombin / Q000008:administration & dosage* / Q000737:chemistry; D046509:Tissue Culture Techniques; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D043925:Angiogenesis Inducing Agents; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; C412222:rusalatide acetate; D013917:Thrombin