Hydrogen sulfide regulation of vascular tone and blood pressure

硫化氢调节血管张力和血压

• 批准号: 8968264
• 负责人: Nancy L Kanagy
• 金额: $ 37.79万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-15 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968264
• 关键词: Adult; American; Animals; Arteries; Beds; Blood; Blood Pressure; Blood Vessels; Blood flow; Blood gas; Calcium; Cardiac Death; Cardiovascular system; Chronic; Cysteine Desulfhydrase; Cytochrome P450; Data; Dilator; Down-Regulation; Endothelial Cells; Endothelium; Exposure to; Future; Generations; Genetic; Genetic Transcription; Goals; Health; Hydrogen Sulfide; Hypertension; Hypotension; Hypoxia; Incidence; Intervention; Kidney; Kidney Failure; Knockout Mice; Knowledge; Laboratory Rat; Left; Mediating; Mesentery; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Oxygen; Pathway interactions; Patients; Peripheral Vascular Diseases; Pilot Projects; Population; Potassium; Potassium Channel; Production; Rattus; Regulation; Risk; Role; Signal Pathway; Signal Transduction; Sleep; Sleep Apnea Syndromes; Smooth Muscle Myocytes; Source; Therapeutic; Time; Tissues; Vascular Diseases; Vascular Smooth Muscle; Vascular resistance; Vasodilation; Vasodilator Agents; autocrine; base; blood pressure reduction; cardiovascular risk factor; endothelial dysfunction; experience; falls; iberiotoxin; mortality; novel; pressure; prevent; prospective; receptor; targeted treatment; therapy development; transcription factor; transcription factor NF-AT c3; vascular bed

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.

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，并增加了患高血压和血管功能障碍的风险。我们已经观察到，通过在睡眠期间将大鼠暴露于间歇性缺氧（IH）来模拟睡眠呼吸暂停，也会增加血压，增强收缩敏感性并损害内皮扩张。这些血管变化似乎部分是由于血管扩张剂硫化氢（H2S）合成的损失。拟议的研究将评估H2S诱导的血管舒张的机制，并确定IH暴露如何损害H2S信号传导以损害血管舒张。H2S是最近描述的由胱硫醚γ-裂解酶（CSE）在脉管系统中产生的血管扩张剂。H2S使血管平滑肌细胞（VSMC）超极化和松弛，但关于其在何处、何时以及如何起作用仍有很多未知。小鼠中CSE的遗传缺失升高血压并损害内皮依赖性扩张，支持其作为血管系统的重要调节剂的作用。我们最近的研究表明，H2S通过激活内皮细胞中的大电导钙敏感性钾通道（BKCa），eBK引起血管舒张。H2S的这种自分泌效应以前没有被研究过，这是本提案的重点。EC中的CSE表达受转录因子NFATc 3调节，并且我们的数据表明IH降低EC中的NFATc 3活化，导致CSE表达降低和H2S诱导的扩张受损。我们的长期目标是确定血管壁中的H2S信号，了解其在血管壁中的调节。 间歇性缺氧，并阐明其在正常和病理性血管功能中的作用。所提出的研究的指导假设是，H2S激活eBK以介导扩张，IH通过降低CSE表达破坏该途径。该项目的第一个目的是评估H2S对内皮细胞中K+通道的激活。第二个目的是确定IH诱导的CSE依赖性血管舒张表达降低的机制。第三个目的是评估H2S对肾、肠系膜和后躯血管床血流的调节，确定IH如何改变调节以导致血压升高。这些研究将在分子、组织和整个动物水平上定义H2S信号，以增加我们对H2S如何有助于心血管控制的理解。确定IH暴露大鼠中H2S信号失调的原因也将为未来开发有效治疗睡眠呼吸暂停人群中高血压和外周血管疾病的疗法提供合理的基础。