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器 压力这些血管感知周向张力的变化， 调节它们的口径，以帮助维持组织灌注，这一过程被称为“肌原性 自动调节”。虽然，肌源性张力通常在动脉的小动脉中缓慢变化， 在心脏和骨骼肌中，肌原性张力非常快。这种速度使这些 器官调节高流速（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， 在初始肌肉收缩后关闭（<1s），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，在心脏 疾病、糖尿病、败血症和衰老，肌原性张力显著下降， 血液动力学、肌肉性能以及对病理学的贡献。底层 能够动态调节肌原性张力的机制是未知的。在这 建议，我们将探讨热门控离子通道，TRPV1的关键作用。我们 使用TRPV1报告小鼠和功能研究相结合的初步数据显示， TRPV1通道特异性定位于心脏中小动脉的平滑肌， 骨骼肌和脂肪。我们假设TRPV1作为一个转导通路， 在小动脉中提供动态肌源性张力的通道。具体来说，我们将测试 TRPV1整合了血流的两种不同性质， 机械感测GPCR下游的刺激和局部血液温度。我们 建议3旨在测试这一创新假设，并了解潜在的 机制等(1)为了验证TRPV1对动态肌源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，（2）为了测试 假设PLC信号和加热是TRPV 1肌源性紧张的基础，（3）为了测试 假设PI（4，5）P2的结合使得持续的TRPV 1活化成为 肌原张力