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.

小动脉小动脉是组织血流和血液的主要调节剂 压力。这些容器感觉到圆周张力的变化，并不断地 调整其口径以帮助维持组织灌注，这一过程称为“肌原性 自动调节”。 心脏和骨骼肌肉，肌原性的张力非常快。这种速度使这些 器官调节高流速（最多占心输出量的85％）以维持 时空灌注。此外，在骨骼肌肉中，动脉音调很快 初始肌肉收缩后的关闭（<1s），以增加血液流动（反应性 高血症），并帮助从休息到运动的过渡。重要的是，在内心 疾病，糖尿病，败血症和衰老，肌原性明显下降，损害 血液动力学，肌肉性能并促进病理学。基础 实现动态调节肌基调的机制尚不清楚。在这个 提案，我们将探索热门离子通道TRPV1的关键作用。我们的 使用TRPV1报告基因小鼠和功能研究的初步数据表明， TRPV1通道专门定位于心脏中动脉的平滑肌， 骨骼肌和脂肪。我们假设TRPV1用作转导 小动脉中的会议动态肌吻合的渠道。具体来说，我们将测试 提议TRPV1整合了两种不同的血流特性，两者都机械 机械感应GPCR和局部血液温度的刺激。我们 提案3旨在检验这一创新的假设并了解基础 机制。 （1）测试TRPV1对于动态肌原态至关重要的假设 在小动脉和动脉平滑肌细胞中的机械传导中，（2）测试 假设PLC信号传导和热量是TRPV1肌吻合的基础，（3）测试 PI（4,5）P2的结合实现了持续的TRPV1激活的假设 肌源性语调。