Cholesterol Metabolism and Angiogenesis: Role of Statins

性状（由申请方提供）：脂质代谢异常， 高血压和血管生成都被证明在 动脉粥样硬化斑块的发展和生长。血管紧张素II已经 显示在体内诱导高血压和动脉粥样硬化， 体外血管生成。初步数据表明，HMGCoA还原酶 抑制剂通过抑制血管生成反应来干扰血管生成 VEGF和FGF-2在血管生成动物模型中的作用。此外，HMGCoA还原酶 抑制剂抑制HUVEC形成毛细血管样结构 在Matrigel上培养和由人真皮上皮形成管 在胶原凝胶上培养的细胞。最后，它们干扰VEGF刺激的 VEGF受体的磷酸化和血管紧张素II对VEGF的诱导 通过抑制一个成员的翻译后脂化在HUVEC中表达 Rho家族的GTP酶。申请人将测试3个假设：1）使用 表达突变型Rho GTP酶的腺病毒载体，申请人将测试 假设血管生成被HMGCoA还原酶抑制剂抑制， 受GTP酶的Rho家族的特定成员调节; 2）VEGF 信号传导是Rho依赖性的，并被HMGCoA还原酶抑制剂抑制， 血管紧张素II、FAK和缺氧各自刺激血管生成并增强 VEGF信号通过对常见的Rho依赖性下游激酶的作用， 被HMGCoA还原酶抑制剂抑制，和3）HMGCoA还原酶 抑制剂干扰VEGF和VEGF受体的表达， 减少新生血管形成和动脉粥样硬化斑块的大小， 胆固醇喂养和血管紧张素II处理的Apo-E-/-小鼠。这些研究将 支持存在一种新的关系，脂质代谢，生长 因子信号传导和高血压，这可能对 动脉粥样硬化的治疗

DESCRIPTION (provided by applicant): Abnormalities of lipid metabolism, hypertension and angiogenesis have all been shown to play a role in the development and growth of atherosclerotic plaques. Angiotensin II has been shown to induce hypertension, and atherosclerosis in vivo and VEGF and angiogenesis in vitro. Preliminary data demonstrate that HMGCoA reductase inhibitors interfere with angiogenesis by inhibiting the angiogenic response to VEGF and FGF-2 in animal models for angiogenesis. Furthermore HMGCoA reductase inhibitors inhibit the formation of capillary-like structures by HUVECs cultured on Matrigel and the formation of tubes by human dermal epithelial cells cultured on a collagen gel. Finally they interfere with VEGF stimulated phosphorylation of VEGF receptors and angiotensin II induction of VEGF expression in HUVECs by inhibiting the posttranslational lipidation of a member of the Rho family of GTPases. The applicant will test 3 hypotheses: 1) using adenoviral vectors expressing mutant Rho GTPases, the applicant will test the hypothesis that angiogenesis is inhibited by HMGCoA reductase inhibitors and regulated by a specific member of the Rho family of GTPases; 2) that VEGF signaling is Rho dependent and inhibited by HMGCoA reductase inhibitors and that angiotensin II, FAK and hypoxia each stimulate angiogenesis and potentiate VEGF signaling via an effect on a common Rho dependent downstream kinase which is inhibited by HMGCoA reductase inhibitors and 3) that HMGCoA reductase inhibitors interfere with the expression of VEGF and VEGF receptors and decrease the neovascularization and the size of atherosclerotic plaques in cholesterol fed and angiotensin II treated Apo-E-/- mice. These studies would support the existence of a new relationship between lipid metabolism, growth factor signaling and hypertension which could have important implications for the treatment of atherosclerosis.