HYPOXIC RESPONSES OF VASCULAR SMOOTH MUSCLE

血管张力的调节涉及两个因素的密切相互作用 血管壁内皮细胞和平滑肌细胞。异常血管 声调和结构是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。低氧可能会对 活化在肺动脉高压发病中的重要作用 特异性基因在人血管内皮细胞中的表达 导致精致的蛋白质产品能够诱导 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，低氧对 平滑肌细胞(SMC)，反过来可以释放介质， 调节内皮细胞(EC)的基因表达。血管SMC 在低氧环境中培养显示出七倍于 血红素加氧酶-p1(NO-1)基因和蛋白的表达。HO催化 血红素分解成一氧化碳(CO)和胆绿素。喜欢 不，CO是一种分子，它能激活Quanyate Cyclase，从而导致 CGMP水平。血管中CGMP水平升高导致SMC 放松一下。推测SMC来源的CO是一种 生理和病理生理状态下的血管张力(如S缺氧) 在一定条件下，SMC来源的Cd可增加血管内皮细胞内cGMP水平 自分泌方式或可调节强效血管活性表达 由内皮细胞产生的介质，如内皮素和PDGF，然后控制 SMC以旁分泌方式生长。这项建议的目的是：研究 常氧和低氧条件下一氧化碳对血管内皮细胞和平滑肌细胞功能的生理作用 低氧条件下，研究HO-基因的分子调控机制 在缺氧性血管SMC中表达。长期的期望是AN 对缺氧性血管SMC的认识。长期的预期是 对控制的基本分子机制的理解 血管张力将加载到新的治疗方法中，以增强身体的适应性 S对低氧的反应。

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.