Hydrogen sulfide regulation of vascular tone and blood pressure

描述（由申请人提供）：据估计，高达20%的美国成年人患有睡眠呼吸暂停，并发高血压和血管功能障碍的风险增加。我们已经观察到，通过在大鼠睡眠期间暴露于间歇性缺氧（IH）来模拟睡眠呼吸暂停，也会增加血压，增强收缩血管的敏感性并损害内皮细胞的扩张。这些血管变化似乎部分是由于血管扩张剂硫化氢（H2S）合成的丧失。拟议的研究将评估H2S诱导血管舒张的机制，并确定IH暴露如何损害H2S信号从而损害血管舒张。H2S是最近发现的一种血管扩张剂，由半胱硫氨酸γ -裂解酶（CSE）在血管中产生。H2S可使血管平滑肌细胞（VSMC）过度极化和松弛，但其作用的地点、时间和方式尚不清楚。小鼠CSE基因缺失会升高血压，损害内皮依赖性扩张，支持其作为血管系统重要调节剂的作用。我们最近的研究表明H2S通过激活内皮细胞（eBK）中的大电导钙敏感钾通道（BKCa）来引起血管舒张。H2S的这种自分泌作用以前没有被研究过，这是本研究的重点。CSE在EC中的表达受转录因子NFATc3的调控，我们的数据表明IH降低了EC中NFATc3的激活，导致CSE表达降低，H2S诱导的扩张受损。我们的长期目标是定义血管壁中的H2S信号，了解其在生长过程中的调控

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.