Systemic Administration of Thrombin Peptide TP508 Enhances VEGF-Stimulated Angiogenesis and Attenuates Effects of Chronic HypoxiaOlszewska-Pazdrak B. · Carney D.H.
aDepartment of Biochemistry and Molecular Biology, The University of Texas Medical Branch, and bChrysalis BioTherapeutics Inc., Galveston, Tex., USA
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.
Prof. Darrell H. Carney
Department of Biochemistry and Molecular Biology
The University of Texas Medical Branch
301 University Blvd., Galveston, TX 77555-0645 (USA)
The authors disclose that D.H.C. owns stock in Chrysalis BioTherapeutics Inc. and that B.O.-P. receives financial support from Chrysalis BioTherapeutics Inc. Potential conflicts of interest are managed by The University of Texas Medical Branch Conflict of Interests Committee.
Received: October 25, 2012
Accepted after revision: January 12, 2013
Published online: April 16, 2013
Number of Print Pages : 11
Number of Figures : 4, Number of Tables : 0, Number of References : 44
Journal of Vascular Research (Incorporating 'International Journal of Microcirculation')
Vol. 50, No. 3, Year 2013 (Cover Date: July 2013)
Journal Editor: Pohl U. (Munich), Meininger G.A. (Columbia, Mo.)
ISSN: 1018-1172 (Print), eISSN: 1423-0135 (Online)
For additional information: http://www.karger.com/JVR