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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/H174    most recent 00699.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Radek, K. A. Articles by DiPietro, L. A. PubMed PubMed Citation Articles by Radek, K. A. Articles by DiPietro, L. A.

Acute ethanol exposure disrupts VEGF receptor cell signaling in endothelial cells

¹Division of Molecular and Cellular Biochemistry, ²Alcohol Research Program, and ³Burn and Shock Trauma Institute, Department of Surgery, Loyola University Medical Center, Maywood, Illinois; ⁴Department of Medicine, University of California, San Diego; and ⁵Center for Wound Healing and Tissue Regeneration, University of Illinois at Chicago, Chicago, Ilinois

Submitted 15 June 2007 ; accepted in final form 2 May 2008

Physiological angiogenesis is regulated by various factors, including signaling through vascular endothelial growth factor (VEGF) receptors. We previously reported that a single dose of ethanol (1.4 g/kg), yielding a blood alcohol concentration of 100 mg/dl, significantly impairs angiogenesis in murine wounds, despite adequate levels of VEGF, suggesting direct effects of ethanol on endothelial cell signaling (40). To examine the mechanism by which ethanol influences angiogenesis in wounds, we employed two different in vitro angiogenesis assays to determine whether acute ethanol exposure (100 mg/dl) would have long-lasting effects on VEGF-induced capillary network formation. Ethanol exposure resulted in reduced VEGF-induced cord formation on collagen and reduced capillary network structure on Matrigel in vitro. In addition, ethanol exposure decreased expression of endothelial VEGF receptor-2, as well as VEGF receptor-2 phosphorylation in vitro. Inhibition of ethanol metabolism by 4-methylpyrazole partially abrogated the effect of ethanol on endothelial cell cord formation. However, mice treated with t-butanol, an alcohol not metabolized by alcohol dehydrogenase, exhibited no change in wound vascularity. These results suggest that products of ethanol metabolism are important factors in the development of ethanol-induced changes in endothelial cell responsiveness to VEGF. In vivo, ethanol exposure caused both decreased angiogenesis and increased hypoxia in wounds. Moreover, in vitro experiments demonstrated a direct effect of ethanol on the response to hypoxia in endothelial cells, as ethanol diminished nuclear hypoxia-inducible factor-1 protein levels. Together, the data establish that acute ethanol exposure significantly impairs angiogenesis and suggest that this effect is mediated by changes in endothelial cell responsiveness to both VEGF and hypoxia.

hypoxia; angiogenesis; alcohol; wound healing