Mechanisms of resistance artery contraction

阻力动脉收缩的机制

• 批准号: 7033535
• 负责人: JOSEPH ELLIOTT BRAYDEN
• 金额: $ 38万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033535
• 关键词: antisense nucleic acid; biological signal transduction; brain circulation; cGMP dependent protein kinase; calcium channel; calcium flux; cerebral artery; cerebrovascular system; confocal scanning microscopy; diacylglycerols; immunochemistry; laboratory rat; membrane potentials; polymerase chain reaction; protein kinase C; protein structure function; tissue /cell culture; vascular endothelium; vascular resistance; vascular smooth muscle; vasoconstriction; voltage /patch clamp; voltage gated channel

DESCRIPTION (provided by applicant): The major objective of this proposal is to elucidate the functional significance of several novel mediators and mechanisms involved in regulating intracellular Ca2+ and contractility of cerebral arteries. Through their constrictor and dilator activity, cerebral arteries tightly regulate blood flow and capillary perfusion pressure within a range that sustains normal brain function. We have discovered that members of the transient receptor potential (TRP) superfamily of ion channels are present in cerebral arteries and that these channels play novel, specific and diverse roles in cerebrovascular function: TRPM4 subserves mechanotransduction. (Aim 1); TRPC3 transduces vasoconstrictor receptor responses (Aim 2); TRPV4 has a unique role in endothelial/smooth muscle communication (Aim 3). We propose to elucidate the properties of these different TRP channels in the cerebral vasculature, and determine their vasoregulatory roles. Specific Aim 1: To define the properties, signal coupling mechanisms, and unique functional roles of TRPM4 channels in cerebral arteries. These experiments will reveal the biophysical properties of TRPM4 channels in native vascular smooth muscle, determine their possible mechanosensitive nature, and consider their in vivo functionality. Specific Aim 2: To elucidate the roles and regulation of native TRPCS channels in agonist induced Ca2+ influx and cerebral vasoconstriction. These experiments will demonstrate the possible role of TRPC3 channels as receptor-operated cation channels in vascular smooth muscle and elucidate the mechanisms by which vascular TRPC3 activity is controlled. Specific Aim 3: To define and differentiate the roles of TRPV4 channels in cerebral arteries. Our preliminary data suggest a novel and unexpected role for TRPV4 channels in endothelium-dependent vasodilator activity, involving endothelium-derived hyperpolarizing factors, TRPV4 channels, and local Ca2+ release events (Ca2+ sparks). In Aim 3 we will reveal the specific mechanisms involved in these responses. The use of multiple, state-of-the-art techniques (membrane potential, cell Ca2+, diameter, ion channel recording, in vivo blood flow measurements, gene silencing) and a unique combination of approaches from the molecular to the whole animal will provide a comprehensive view of the role of TRP channels in the cerebral circulation and indicate novel targets for agents that could be used to correct pathological alterations in cerebral blood flow.

描述（由申请人提供）：本提案的主要目的是阐明参与调节细胞内 Ca2+ 和脑动脉收缩性的几种新型介质和机制的功能意义。通过其收缩器和扩张器活动，脑动脉将血流量和毛细血管灌注压严格调节在维持正常脑功能的范围内。我们发现，离子通道瞬时受体电位 (TRP) 超家族的成员存在于脑动脉中，并且这些通道在脑血管功能中发挥着新颖、特异和多样化的作用：TRPM4 有助于机械转导。 （目标 1）； TRPC3 转导血管收缩受体反应（目标 2）； TRPV4 在内皮/平滑肌通讯中具有独特的作用（目标 3）。我们建议阐明脑血管系统中这些不同 TRP 通道的特性，并确定它们的血管调节作用。具体目标 1：明确脑动脉中 TRPM4 通道的特性、信号耦合机制和独特的功能作用。这些实验将揭示天然血管平滑肌中TRPM4通道的生物物理特性，确定它们可能的机械敏感性性质，并考虑它们的体内功能。具体目标 2：阐明天然 TRPCS 通道在激动剂诱导的 Ca2+ 内流和脑血管收缩中的作用和调节。这些实验将证明 TRPC3 通道作为血管平滑肌中受体操纵的阳离子通道的可能作用，并阐明控制血管 TRPC3 活性的机制。具体目标 3：定义和区分 TRPV4 通道在脑动脉中的作用。我们的初步数据表明 TRPV4 通道在内皮依赖性血管舒张活性中具有新颖且意想不到的作用，涉及内皮衍生的超极化因子、TRPV4 通道和局部 Ca2+ 释放事件（Ca2+ 火花）。在目标 3 中，我们将揭示这些反应所涉及的具体机制。使用多种最先进的技术（膜电位、细胞 Ca2+、直径、离子通道记录、体内血流测量、基因沉默）以及从分子到整个动物的独特方法组合，将提供 TRP 通道在脑循环中的作用的全面视图，并为可用于纠正脑血流病理改变的药物指明新的靶点。