Acute ethanol exposure disrupts VEGF receptor cell signaling in endothelial cells
Acute ethanol exposure disrupts VEGF receptor cell signaling in endothelial cells
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DOI：
10.1152/ajpheart.00699.2007
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发表时间：
2008-07-01
影响因子：
4.8
通讯作者：
DiPietro, Luisa A.
中科院分区：
文献类型：
--
作者：
Radek, Katherine A.;Kovacs, Elizabeth J.;DiPietro, Luisa A.
生理性血管生成受多种因素调节，包括通过血管内皮生长因子 (VEGF) 受体发出的信号。我们之前报道过，尽管 VEGF 水平足够，但单剂量乙醇 (1.4 g/kg) 产生的血液酒精浓度为 100 mg/dl，会显着损害小鼠伤口的血管生成，这表明乙醇对内皮细胞信号传导有直接影响 (40)。为了研究乙醇影响伤口血管生成的机制，我们采用了两种不同的体外血管生成测定法来确定急性乙醇暴露（100 mg/dl）是否会对 VEGF 诱导的毛细血管网络形成产生长期影响。体外，乙醇暴露导致 VEGF 诱导的胶原索形成减少，基质胶上毛细血管网络结构减少。此外，乙醇暴露降低了内皮 VEGF 受体 2 的表达以及体外 VEGF 受体 2 的磷酸化。 4-甲基吡唑对乙醇代谢的抑制部分消除了乙醇对内皮细胞索形成的影响。然而，用叔丁醇（一种不被乙醇脱氢酶代谢的醇）治疗的小鼠，伤口血管分布没有变化。这些结果表明，乙醇代谢产物是乙醇诱导的内皮细胞对 VEGF 反应性变化发展的重要因素。在体内，乙醇暴露会导致血管生成减少和伤口缺氧增加。此外，体外实验证明乙醇对内皮细胞缺氧反应有直接影响，因为乙醇降低了核缺氧诱导因子 1 α 蛋白水平。总之，数据表明，急性乙醇暴露会显着损害血管生成，并表明这种效应是由内皮细胞对 VEGF 和缺氧的反应性变化介导的。
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 alpha 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.