Vasorelaxation effect and mechanism of action of vascular endothelial growth factor-165 in isolated perfused human skin flaps.

Abstract

BACKGROUND:

Experimental evidence is accumulating to indicate that local acute vascular endothelial growth factor-165 (VEGF(165)) therapy is effective in attenuation of skin ischemia and increase in skin viability in rat skin flap surgery and the mechanism involves vasodilation induced by VEGF(165). So far, the vasodilator effect and mechanism of action of VEGF(165) have not been studied in human skin. The objective of this project is to test the hypothesis that VEGF(165) is also a potent vasodilator in human skin vasculature.

MATERIALS AND METHODS:

We used an established isolated perfused human skin flap model and pharmacologic probes to demonstrate that VEGF(165) is a potent vasodilator in human skin vasculature and the mechanism involves activation of receptors and postreceptor signaling pathway, which in turn stimulates local synthesis/release of endothelial vasodilators.

RESULTS:

We observed that VEGF(165) induced a concentration-dependent vasorelaxation in human skin flaps preconstricted with norephinephrine (8 × 10(-7)M; n = 7) or endothelin-1 (3 × 10(-9)M; n = 6). The vasorelaxation potency of VEGF(165) (pD(2) = 12.02 ± 0.25; n = 7) was higher (P < 0.05) than that of acetylcholine (pD(2) = 6.76 ± 0.06; n = 5) in human skin flaps preconstricted with 8 x 10(-7)M of norepinephrine. Using pharmacologic probes, we also detected that the vasorelaxation effect of VEGF(165) in the isolated perfused human skin flaps (n = 4) was triggered by activation of VEGF receptor-2. Furthermore, the postreceptor signaling pathway involved activation of Src family tyrosine kinase, phospholipase C, protein kinase C, an increase in inositol 1,4,5-triphosphate activity, a release of the intracellular Ca(2+) store, and finally synthesis/release of the endothelial nitric oxide (eNO) and prostacyclin and eNO predominantly mediated the vasodilator effect of VEGF(165) in the effector mechanism.

CONCLUSION:

These findings support our hypothesis that VEGF(165) is a potent vasodilator in human skin vasculature and also provide important insights into the clinical study of local acute VEGF(165) therapy for prevention/treatment of skin ischemia in skin flap surgery.

• Authors: Ning Huang, Homa Ashrafpour, Ronald H Levine, Christopher R Forrest, Peter C Neligan, Joan E Lipa, Cho Y Pang
• Journal: The Journal of surgical research (J Surg Res) Vol. 172 Issue 1 Pg. 177-86 (Jan 2012) ISSN: 1095-8673 [Electronic] United States
• PMID: 20934716 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Vasodilator Agents
• Nitric Oxide
• Epoprostenol
• Receptor Protein-Tyrosine Kinases

Topics

• Dose-Response Relationship, Drug
• Epoprostenol (metabolism)
• Humans
• In Vitro Techniques
• Ischemia (prevention & control)
• Nitric Oxide (metabolism)
• Receptor Protein-Tyrosine Kinases (drug effects)
• Regional Blood Flow (drug effects)
• Signal Transduction (drug effects)
• Skin (blood supply, drug effects)
• Surgical Flaps (blood supply)
• Vascular Endothelial Growth Factor A (pharmacology, therapeutic use)
• Vasodilation (drug effects)
• Vasodilator Agents (pharmacology, therapeutic use)