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1 Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
2 Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada
3 Department of Surgery, University of Toronto, Toronto, Ontario, Canada
4 Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: pang{at}sickkids.ca.
Various laboratories reported that local subcutaneous or subdermal injection of VEGF165 at the time of surgery effectively attenuated ischemic necrosis in rat skin flaps, but the mechanism was not studied and enhanced angiogenesis was implicated. In the present studies, we used the clinically relevant isolated perfused 6 x 16 cm pig buttock skin flap model to: (i) test our hypothesis that VEGF165 is a potent vasodilator and acute VEGF165 treatment increases skin perfusion; and (ii) investigate the mechanism of VEGF165-induced skin vasorelaxation. We observed that VEGF165 (5 x 10-16 - 5 x 10-11M) elicited a concentration-dependent decrease in perfusion pressure (i.e. vasorelaxation) in skin flaps preconstricted with a submaximal concentration of norepinephrine (NE), endothelin-1 or U46619. The VEGF165-induced skin vasorelaxation was confirmed using a dermofluorometry technique for assessment of skin perfusion. The vasorelaxation potency of VEGF165 in NE-preconstricted skin flaps (pD2=13.57 ± 0.31) was higher (p<0.05) than that of acetylcholine (pD2 = 7.08 ± 0.24). The human placental factor, a specific VEGF receptor-1 agonist, did not elicit any vasorelaxation effect. However, a specific antibody to VEGF receptor-2 (1 µg/ml) or a specific VEGF receptor-2 inhibitor (SU 1498, 5 x 10-6M) blocked the vasorelaxation effect of VEGF165 in NE-preconstricted skin flaps. These observations indicate that the potent vasorelaxation effect of VEGF165 in skin vasculature is initiated by activation of the VEGF receptor-2. Furthermore, using pharmacologic probes, we observed that the postreceptor signaling pathways of VEGF165-induced skin vasorelaxation involved activation of phospholipase C and protein kinase C, increase in inositol 1, 4, 5-triphosphate activity, release of intracellular Ca2+ store, and synthesis/release of endothelial nitric oxide which predominantly triggered the effector mechanism of VEGF165-induced vasorelaxation. This information provides, for the first time, an important insight into the mechanism of VEGF165 protein or gene therapy in prevention/treatment of ischemia in skin flap surgery and skin ischemic diseases.
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