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量和血液的主要调节器 压力。这些血管感觉到周向张力的变化并持续 调整口径以帮助维持组织灌流，这一过程被称为“肌源性” 自动调节“。虽然，肌源性张力通常变化缓慢的小动脉。 心脏和骨骼肌，肌张力非常快。这一速度使这些 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，动脉张力很快就会改变 在初始肌肉收缩后关闭(&lt；1s)以增加血流量(反应性 充血)，并有助于从休息到运动的过渡。重要的是，在心跳 疾病、糖尿病、败血症和衰老，肌源性张力明显下降，损害 血流动力学、肌肉表现和病理改变。潜在的 实现肌源性张力动态调节的机制尚不清楚。在这 提案中，我们将探索热门离子通道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显示 TRPV1通道特异性地定位于心脏小动脉的平滑肌， 骨骼肌和脂肪。我们假设TRPV1作为一种转导 在小动脉中提供动态肌源性张力的通道。具体地说，我们将测试 提出TRPV1整合了血流的两种不同性质，都是机械的 机械感应GPCRs下游的刺激，以及局部血液温度。我们 提案3旨在检验这一创新假设，并理解潜在的 机制。(1)验证TRPV1对动态肌源性张力起关键作用的假设 在小动脉和动脉平滑肌细胞中的机械转导，(2)测试 假设PLC信号和热是TRPV1肌源性张力的基础，(3)测试 假设PI(4，5)P2的结合使TRPV1能够持续激活 生肌性音调。