HYPOXIC RESPONSES OF VASCULAR SMOOTH MUSCLE

描述（逐字摘自研究者摘要）：异常血管光滑 肌细胞（VSMC）增殖是血管疾病的关键特征， 肺动脉高压和动脉粥样硬化。低氧条件下VSMC生长增加 是作用于血管壁的复杂反馈回路机制的结果。 缺氧可增加VSMC血红素氧合酶-1（HO-1）基因的表达。 HO-1催化血红素的分解，导致血红素的形成。 血管扩张剂CO和抗氧化剂胆红素。像NO一样，CO激活鸟苷酰 环化酶导致cGMP水平升高，进而导致VSMC松弛 并限制VSMC增殖。我们的数据显示， VSMC，（1）抑制内皮细胞衍生的缺氧诱导 有丝分裂原，内皮素和血小板衍生生长因子-B，间接 抑制VSMC增殖;（2）CO也抑制VSMC增殖 通过抑制E2 F-1的表达， 周期特异性转录因子;和（3）抑制反式激活 缺氧诱导因子-1在缺氧基因表达中的作用基于 根据这些观察结果，我们假设VSMC衍生的CO是一种生理性的 血管内环境稳定的调节器。为此，我们创建并建议 使用HO-1条件性器官特异性表达的转基因小鼠， 研究这种重要分子的生理学。我们长远的目标是 了解CO如何调节生理条件下的内皮-VSMC相互作用， 缺氧的病理生理条件提供了新的基础 用于治疗血管疾病的治疗策略， 肺动脉高压和动脉粥样硬化。我们提出以下具体建议： 目的：（1）探讨缺氧基因调控的分子机制， （2）明确CO在肺血管维持中的作用 体内平衡(3)探讨HO-1在血管损伤中的作用。

DESCRIPTION (Verbatim from Investigator's Abstract): Abnormal vascular smooth muscle cell (VSMC) proliferation is a key feature of vascular diseases such as pulmonary hypertension and atherosclerosis. Increased VSMC growth under hypoxia is the result of complex feedback loop mechanisms acting on the vessel wall. Hypoxia increases the expression of the heme oxygenase-1 (HO-1) gene by VSMC. HO-1 catalyzes the breakdown of heme leading to the formation of the vasodilator CO and the antioxidant, bilirubin. Like NO, CO activates guanylyl cyclase resulting in elevated cGMP levels which in turn cause VSMC relaxation and limit VSMC proliferation. Our data show that it is the increase in CO by VSMC that (1) inhibits the hypoxic induction of the endothelial cell-derived mitogens, endothelin and platelet derived growth factor-B, indirectly inhibiting VSMC proliferation; (2) that CO also suppresses VSMC proliferation independent of endothelial cells by inhibiting the expression of E2F-1, a cell cycle-specific transcription factor; and (3) inhibits the trans-activating function of hypoxia-inducible factor-1 on gene expression by hypoxia. Based on these observations, we hypothesize that VSMC-derived CO is a physiologic regulator of vascular homeostasis. For this reason, we have created and propose to use transgenic mice with conditional, organ-specific expression of HO-1 to study the physiology of this important molecule. Our long-term objective is to understand how CO modulates endothelial-VSMC interactions under physiologic and pathophysiologic conditions of hypoxia to provide the basis of novel therapeutic strategies for the treatment of vascular disorders such as pulmonary hypertension and atherosclerosis. We propose the following specific aims: (1) To investigate the molecular mechanisms of hypoxic gene regulation by CO. (2) To define the role of CO in the maintenance of pulmonary vascular homeostasis. (3) To define the role of HO-1 in vascular injury.