Hydrogen sulfide regulation of vascular tone and blood pressure

描述(申请人提供)：据估计，多达20%的美国成年人患有睡眠呼吸暂停，患高血压和血管功能障碍的风险增加。我们观察到，通过在睡眠中暴露于间歇性低氧(IH)来模拟大鼠睡眠呼吸暂停，也会增加血压，增强收缩肌的敏感性，并损害血管内皮的扩张。这些血管变化似乎部分是由于血管扩张剂硫化氢(H_2S)合成的丧失。拟议的研究将评估H_2S诱导的血管扩张的机制，并确定暴露于H_2S如何损害H_2S信号从而损害血管扩张。硫化氢是一种新近被描述的血管扩张剂，在血管系统中由胱硫醚伽玛裂解酶(CSE)产生。硫化氢使血管平滑肌细胞(VSMC)超极化和松弛，但它在哪里、何时和如何发挥作用仍有许多未知之处。在小鼠中，CSE基因缺失会升高血压，损害内皮依赖性的扩张，支持其作为血管系统重要调节因子的作用。我们最近的研究表明，硫化氢通过激活内皮细胞的大电导钙敏感钾通道(BKCa)引起血管扩张。硫化氢的这种自分泌效应以前没有被研究过，也是这项提议的重点。EC中CSE的表达受转录因子NFATc3的调控，我们的研究结果表明，IH降低了EC中NFATc3的激活，导致CSE的表达减少，并抑制了H_2S诱导的血管扩张。我们的长期目标是定义血管壁中的硫化氢信号，了解其在 间歇性低氧并阐明其在正常和病理血管功能中的作用。这项研究的指导假设是，硫化氢激活eBK以调节扩张，而IH通过减少CSE的表达来破坏这一途径。该项目的第一个目标是评估硫化氢对内皮细胞K+通道的激活作用。第二个目的是确定IH导致CSE依赖的血管扩张表达减少的机制。第三个目的是评估H_2S对肾、肠系膜和后肢血管床血流的调节，以确定IH如何改变调节从而导致血压升高。总之，拟议的研究将在分子、组织和整个动物水平上定义硫化氢信号，以增加我们对硫化氢如何有助于心血管控制的理解。明确高血压大鼠硫化氢信号转导失调的原因也将为未来针对有效治疗睡眠呼吸暂停人群高血压和外周血管疾病的治疗方法的发展提供合理的基础。

DESCRIPTION (provided by applicant): It is estimated that up to 20% of American adults suffer from sleep apnea with an increased risk of developing hypertension and vascular dysfunction. We have observed that simulating sleep apnea in rats by exposing them to intermittent hypoxia (IH) during sleep also increases blood pressure, augments constrictor sensitivity and impairs endothelial dilation. These vascular changes appear to be due in part to loss of the synthesis of the vasodilator, hydrogen sulfide (H2S). Proposed studies will evaluate the mechanisms of H2S- induced vasodilation and determine how IH exposure impairs H2S signaling to impair vasodilation. H2S is a recently described vasodilator produced in the vasculature by cystathionine gamma-lyase (CSE). H2S hyperpolarizes and relaxes vascular smooth muscle cells (VSMC) but much is still unknown about where, when and how it acts. Genetic deletion of CSE in mice elevates blood pressure and impairs endothelium- dependent dilation supporting its role as an important regulator of the vasculature. Our recent studies reveal that H2S causes vasodilation by activating large-conductance calcium-sensitive potassium channels (BKCa) in endothelial cells, eBK. This autocrine effect of H2S has not previously been investigated and is the focus of this proposal. CSE expression in EC is regulated by the transcription factor, NFATc3 and our data suggest IH decreases NFATc3 activation in EC leading to decreased CSE expression and impaired H2S- induced dilation. Our long term goal is to define H2S signaling in the vascular wall, to understand its regulation during intermittent hypoxia and to clarify its role in normal and pathological vascular function. The guiding hypothesis for the proposed studies that H2S activates eBK to mediate dilation and that IH disrupts this pathway by decreasing CSE expression. The first Aim of the project is to evaluate H2S activation of K+ channels in endothelial cells. The second Aim is to define the mechanism IH-induced decreases in CSE-dependent vasodilation expression. The third Aim is to Evaluate H2S regulation of blood flow in renal, mesenteric and hindquarters vascular beds determine how IH alters the regulation to contribute to elevated blood pressure. Together the proposed studies will define H2S signaling at molecular, tissue and whole animal levels to increase our understanding of how H2S contributes to cardiovascular control. Defining the causes of dysregulated H2S signaling in IH-exposed rats will also provide a rational basis for the future development of therapies targeting to effectively treat hypertension and peripheral vascular disease in the sleep apnea population.