HYPOXIC RESPONSES OF VASCULAR SMOOTH MUSCLE

血管张力的调节涉及以下因素之间的密切相互作用： 血管壁中的内皮细胞和平滑肌细胞。 异常血管 这些重要疾病的病理生理学基础 如肺动脉高压和动脉粥样硬化。 缺氧可能会导致 在肺动脉高压的发病机制中起重要作用， 人血管内皮细胞特异基因的表达 导致蛋白质产物的加工， 血管收缩、平滑肌细胞增生和基质重塑。 此外，他们最近的研究表明，缺氧对 平滑肌细胞（SMC）又可以释放介质， 调节内皮细胞（EC）中的基因表达。 血管平滑肌细胞 在低氧环境中培养的小鼠， 血红素氧合酶-p1（NO-1）mRNA和蛋白表达。 HO催化 血红素分解产生一氧化碳和胆绿素。 像 NO、CO是一种激活量子酸环化酶的分子， cGMP水平。 血管系统中CGMP水平升高导致SMC 放松. 据推测，SMC衍生的CO是一种调节剂， 生理和病理生理条件下的血管张力（如缺氧） SMC衍生的CD可以增加细胞内cGMP水平， 自分泌方式或可调节血管活性物质的表达 内皮细胞产生的介质如内皮素和PDGF， SMC以旁分泌方式生长。 本提案的目的是： 常氧和低氧条件下CO对EC和SMC功能生理作用 低氧条件下，并检查控制HO-基因的分子机制 缺氧血管平滑肌细胞表达。 长期的期望是 了解缺氧血管SMC。 长期的预期是， 了解控制的基本分子机制 血管张力将加载到新的疗法，以提高身体的适应性 对缺氧的反应。

Regulation of vascular tone involves the close interaction between endothelial and smooth muscle cells in the vessel wall. Abnormal vessel tone and structure underlie the pathophysiology of such important diseases as pulmonary hypertension and atherosclerosis. Hypoxia may play an important role in the pathogenesis of pulmonary hypertension by activating the expression of specific genes in human vascular endothelial cells resulting in the elaboration of protein products able to induce vasoconstriction, smooth muscle cell hyperplasia, and matrix remodeling. In addition, their recent studies show that hypoxia has direct effects on the smooth muscle cells (SMC), which in turn, can release mediators that regulate gene expression in the endothelial cells (EC). Vascular SMC cultured in a hypoxic environment demonstrated a seven-fold increase in the expression of the heme oxygenases-p1 (NO-1) mRNA and protein. HO catalyzes the breakdown of heme to yield carbon monoxide (CO) and biliverdin. Like NO, CO is a molecule that activates quanylate cyclase resulting in elevated cGMP levels. Increased CGMP levels in the vasculature causes SMC relaxation. It is hypothesized that SMC-derived CO is a regulator of vascular tone under physiologic and pathophysiologic (such s hypoxic) conditions, SMC-derived CD can increase intracellular cGMP levels in an autocrine manner or it can regulate the expression of potent vasoactive mediators produced by E C such as endothelin and PDGF which then control SMC growth in a paracrine manner. The aims of this proposal are: To study the physiologic role of CO on EC and SMC function under normoxic and hypoxic conditions, and to examine molecular mechanisms controlling HO-gene expression in hypoxic vascular SMC. The long-term expectation is the an understanding of hypoxic vascular SMC. The long-term expectation is that an understanding of the basic molecualr mechanisms responsible for control vascular tone will load to new therapies to enhance the body a adaptive response s to hypoxia.