MECHANISMS UNDERLYING ARTERIOLAR MYOGENIC CONTRACTION

生肌机制在局部血流控制中的作用 血管阻力近年来受到了极大的关注。 然而，关于细胞内事件的信息很少， 将小动脉的收缩反应与 血管内压 本提案的总体目标是 研究细胞内信号通路， 肌原性反应 四个具体的假设将被检查：1。的 小动脉收缩器的Ca2+敏感性是一个函数， 血管内压力，2。维持肌原性的 小动脉的收缩依赖于蛋白质的参与， 激酶C介导的途径，3.这些通路控制着细胞内 血管平滑肌的Ca2+敏感性和Ca2+需求 在收缩的维持阶段期间的收缩器，以及 4.暴露于血管扩张剂后对Ca2+的脱敏提供了 肌源性反应可以部分，或完全， 被适当的代谢刺激所抑制。 其中的一个必要组成部分 研究将描述细胞内 钙水平和小动脉肌源性收缩的程度。 一 分离的微血管和图像分析技术的组合将是 用来研究这些假设。 拟议的调查将 补充我们以前的体内微循环研究， 细胞生物化学事件与先前记录的 生理现象。 细胞内途径的知识， 肌源性反应将使我们能够更全面地了解血液流动 自身调节，包括代谢和肌生成之间的相互作用 刺激，也将提供深入了解的机制，基础 小动脉张力 此外，了解这些基本机制， 有助于解释肌源性机制在血管 与诸如高血压和糖尿病的疾病状态相关的病理学 微血管病变，并可能确定新的药理学 干预

The role of myogenic mechanisms in the control of local blood flow and vascular resistance has received a great deal of attention in recent years. However, little information exists as to the intracellular events which couple the contractile response of an arteriole to an acute rise in intravascular pressure. The overall goal of this proposal is to investigate intracellular signalling pathways which are involved in the myogenic response. Four specific hypotheses will be examined: 1. that Ca2+ sensitivity of the contractile apparatus in arterioles is a function of intravascular pressure, 2. that the maintenance of a myogenic constriction in small arterioles is dependent on the involvement of protein kinase C mediated pathways, 3. that such pathways control the intracellular Ca2+ sensitivity, and thus Ca2+ requirements, of the vascular smooth muscle contractile apparatus during the maintained phase of the contraction, and 4. that desensitization to Ca2+ following exposure to vasodilators provides a mechanism whereby the myogenic response can be partially, or completely, inhibited by appropriate metabolic stimuli. A necessary component of these studies will be the description of the relationship between intracellular calcium levels and the extent of arteriolar myogenic contraction. A combination of isolated microvessel and image analysis techniques will be used to investigate that hypotheses. The proposed investigation will complement our previous in vivo studies of the microcirculation by allowing the integration of cellular biochemical events with previously documented physiologic phenomena. Knowledge of the intracellular pathways involved in the myogenic response will enable us to more fully understand blood flow autoregulation, including the interactions between metabolic and myogenic stimuli, and will also provide insight into mechanisms which underlie basal arteriolar tone. Understanding these basic mechanisms will, in addition, assist in interpreting the role of myogenic mechanisms in the vascular pathology associated with disease states such as hypertension and diabetic microangiopathy and may identify sites for novel pharmacologic intervention.