TRPV1 and the regulation of arterial tone

TRPV1 和动脉张力的调节

• 批准号: 10299144
• 负责人: GERARD P AHERN
• 金额: $ 39万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299144
• 关键词: Adipose tissue; Affect; Afferent Neurons; Aging; Agonist; Arteries; Binding; Binding Sites; Blood; Blood Pressure; Blood flow; Caliber; Cardiac Output; Cells; Data; Diabetes Mellitus; Exercise; Feedback; G-Protein-Coupled Receptors; Genetic; Heart; Heart Diseases; Hindlimb; Homeostasis; Hyperemia; Impairment; Ion Channel; Ion Channel Gating; Ischemia; Knock-in; Knockout Mice; Limb structure; Maps; Mechanics; Mediating; Mus; Muscle; Muscle Cells; Muscle Contraction; Myocardium; Organ; Pathology; Pathway interactions; Performance; Perfusion; Peripheral; Pharmacology; Phosphatidylinositols; Phospholipase C; Phosphorylation; Physiological; Process; Property; Protons; Regulation; Reporter; Resistance; Rest; Role; Sepsis; Signal Transduction; Skeletal Muscle; Smooth Muscle; Smooth Muscle Myocytes; Speed; Stimulus; Stretching; System; TRPV1 gene; Temperature; Testing; Tissues; Vascular Smooth Muscle; Vasodilation; arteriole; density; desensitization; hemodynamics; in vivo; innovation; intravital imaging; mechanotransduction; mutant; optogenetics; pressure; prevent; reactive hyperemia; response; spatiotemporal; stoichiometry; vasoconstriction; voltage clamp

Small resistance arterioles are the principal regulators of tissue blood flow and blood pressure. These vessels sense changes in circumferential tension and continuously adjust their caliber to help maintain tissue perfusion, a process termed “myogenic autoregulation”. Although, myogenic tone usually changes slowly in arterioles of the heart and skeletal muscle, the myogenic tone is very rapid. This speed allows these organs to regulate high flow rates (up to 85% of cardiac output) to maintain spatiotemporal perfusion. Further, in skeletal muscle, the arterial tone is quickly turned off (<1s) after an initial muscle contraction to allow increased blood flow (reactive hyperemia), and aid the transition from rest to exercise. Importantly, during heart disease, diabetes, sepsis and ageing, myogenic tone markedly declines, impairing hemodynamics, muscle performance and contributing to pathology. The underlying mechanisms that enable dynamic regulation of myogenic tone are unknown. In this proposal, we will explore a critical role for the heat-gated ion channel, TRPV1. Our preliminary data, using TRPV1 reporter mice and functional studies combined, show that TRPV1 channels specifically localize to the smooth muscle of arterioles in the heart, skeletal muscle and adipose. We hypothesize that TRPV1 serves as a transduction channel to confer dynamic myogenic tone in small arterioles. Specifically, we will test the proposal that TRPV1 integrates two distinct properties of blood flow, both mechanical stimuli downstream of mechanosensing GPCRs, and the local blood temperature. We propose 3 aims to test this innovative hypothesis and to understand the underlying mechanisms. (1) To test the hypothesis that TRPV1 is critical for dynamic myogenic tone in small arteries and mechanotransduction in arterial smooth muscle cells, (2) To test the hypothesis that PLC signaling and heat underlie TRPV1 myogenic tone, (3) To test the hypothesis that binding of PI(4,5)P2 enables persistent TRPV1 activation necessary for myogenic tone.

小阻力小动脉是组织血流和血液的主要调节者 压力。这些血管感知周向张力的变化并持续 调整它们的口径以帮助维持组织灌注，这一过程被称为“肌源性” 自我调节”。尽管如此，肌源性张力通常在小动脉中缓慢变化 心脏和骨骼肌的肌源性张力非常快。这个速度允许这些 器官调节高流量（高达心输出量的 85%）以维持 时空灌注。此外，在骨骼肌中，动脉张力迅速转变 初始肌肉收缩后关闭（<1秒）以允许增加血流量（反应性 充血），并帮助从休息到运动的过渡。重要的是，在心里 疾病、糖尿病、败血症和衰老，肌源性张力显着下降，损害 血流动力学、肌肉性能和对病理学的贡献。底层的 能够动态调节肌源性张力的机制尚不清楚。在这个 在提案中，我们将探索热门控离子通道 TRPV1 的关键作用。我们的 使用 TRPV1 报告小鼠和功能研究相结合的初步数据表明 TRPV1 通道专门定位于心脏小动脉的平滑肌， 骨骼肌和脂肪。我们假设 TRPV1 作为转导 通道赋予小动脉动态肌原性张力。具体来说，我们将测试 TRPV1 整合了血流的两种不同特性，即机械特性 机械传感 GPCR 下游的刺激以及局部血液温度。我们 提议 3 旨在检验这一创新假设并了解其背后的原理 机制。 (1) 检验 TRPV1 对于动态肌原性张力至关重要的假设 在小动脉和动脉平滑肌细胞的机械转导中，（2）测试 假设 PLC 信号传导和热量是 TRPV1 肌原性张力的基础，(3) 测试 假设 PI(4,5)P2 的结合能够实现 TRPV1 的持续激活，这是 肌源性音调。