Nitric Oxide-Mediated Pulmonary Vasodilation After Chronic Hypoxia

慢性缺氧后一氧化氮介导的肺血管舒张

• 批准号: 7236634
• 负责人: THOMAS C RESTA
• 金额: $ 32万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7236634
• 关键词: Nitric; Oxide; Mediated; Pulmonary; Vasodilation

DESCRIPTION (provided by applicant): Chronic hypoxia (CH) associated with various lung diseases leads to pulmonary hypertension. Adaptive responses, including enhanced nitric oxide (NO)-mediated vasodilation, may diminish the severity of hypoxic pulmonary hypertension. However, neither the mechanism of altered NO-dependent reactivity following CH, nor the signaling pathways leading to NO-mediated pulmonary vasodilation are well understood. Protein kinase G (PKG) is a prominent target of NO signaling that elicits relaxation of vascular smooth muscle (VSM) by decreasing the concentration of intracellular free calcium ([Ca 2+]i)as well as desensitization of the contractile apparatus to Ca 2+ . This latter effect of PKG to cause Ca2+-desensitization is largely undefined, although studies have implicated a role for inactivation of the RhoA-Rho kinase-signaling cascade in this response. Interestingly, pilot experiments suggest that CH attenuates PKG-dependent decreases in VSM [Ca 2+]i while paradoxically augmenting PKG-mediated vasodilation. Therefore, the proposed studies will investigate the central hypothesis that CH impairs PKG-dependent regulation of [Ca2+]i in pulmonary VSM and mediates a compensatory shift in PKG signaling to promote desensitization of the contractile apparatus to [Ca 2+]. This hypothesis will be addressed by the following specific aims: Specific Aim #1: Establish the mechanism by which CH impairs PKG-dependent reduction of pulmonary VSM [Ca2+]i. The working hypothesis for this aim is that CH diminishes PKG-mediated decreases in VSM [Ca2+]i by interfering with regulation of Ca 2+ influx and sequestration mechanisms. Specific Aim #2: Identify the mechanism by which CH augments PKG-mediated pulmonary VSM Ca2+-desensitization. We hypothesize that enhanced PKG-mediated pulmonary vasodilation following CH is a function of VSM Ca2+-desensitization through inhibition of the RhoA-Rho kinase pathway. The proposed studies will employ an innovative approach to address mechanisms by which CH alters PKG-signaling in pulmonary VSM, including simultaneous measurement of vasoreactivity and VSM [Ca2+]i in isolated, pressurized small pulmonary arteries from control and CH rats. Findings from studies are expected to fundamentally advance our understanding of signal transduction mechanisms by which PKG regulates pulmonary vascular tone, as well as adaptive responses of the pulmonary circulation to CH.

描述（由申请人提供）：与各种肺部疾病相关的慢性缺氧（CH）导致肺动脉高压。自适应反应，包括增强的一氧化氮（NO）介导的血管舒张，可能会减少低氧肺动脉高压的严重程度。但是，CH后无依赖性反应性改变的机制，以及导致NO介导的肺血管舒张的信号传导途径。蛋白激酶G（PKG）是没有信号传达的一个突出靶标，即通过降低细胞内游离钙（[Ca 2+] I）的浓度以及使收缩式Applatus脱敏的浓度来引起血管平滑肌（VSM）的松弛。 PKG引起Ca2+脱敏化的后一种效应在很大程度上是不确定的，尽管研究暗示了将Rhoa-Rho激酶信号级联级联反激活的作用。有趣的是，试点实验表明，VSM [Ca 2+] I的CH降低了PKG依赖性的降低，同时矛盾地增强PKG介导的血管舒张。因此，拟议的研究将研究肺VSM中[Ca2+] I的PKG依赖性调节的中心假设，并介导PKG信号的代偿性转移，以​​促进收缩仪对[Ca 2+]的脱敏。该假设将通过以下特定目的来解决：特定目的＃1：建立CH损害肺VSM的PKG依赖性减少的机制[Ca2+] i。此目的的工作假设是，通过干扰调节Ca 2+的流入和隔离机制，CH会减少VSM [Ca2+] I的PKG介导的降低。特定目的＃2：确定CH扩大PKG介导的肺VSM CA2+ - 敏感的机制。我们假设CH后增强的PKG介导的肺血管舒张是通过抑制Rhoa-Rho激酶途径的VSM Ca2+ - 脱敏化的函数。拟议的研究将采用一种创新的方法来解决CH在肺VSM中改变PKG信号的机制，包括同时测量血管反应性和VSM [Ca2+] I中的[Ca2+] I中的[Ca2+] I中的分离，由对照和CH大鼠的分离，加压的小肺动脉。预计从研究的结果从根本上可以提高我们对PKG调节肺血管张力的信号转导机制的理解，以及肺循环对CH的自适应反应。