Mechanisms of resistance artery contraction

阻力动脉收缩的机制

• 批准号: 7568757
• 负责人: JOSEPH ELLIOTT BRAYDEN
• 金额: $ 36.9万
• 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/7568757
• 关键词: Agonist; Animals; Antisense Oligonucleotides; Arteries; Arts; Behavior; Blood Vessels; Blood capillaries; Blood flow; Brain; Calcium; Calcium Channel; Caliber; Cardiovascular system; Cations; Cell membrane; Cells; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrum; Communication; Coupling; Data; Dilator; Endothelial Cells; Endothelium; Endothelium-Dependent Relaxing Factors; Event; Family; Fingerprint; Gene Silencing; Homeostasis; Hormonal; In Vitro; Ion Channel; Knockout Mice; L-Type Calcium Channels; Life; Link; Measurement; Mechanics; Mediating; Mediator of activation protein; Membrane; Membrane Potentials; Methodology; Modeling; Molecular; Monovalent Cations; Muscle Cells; Nature; Normal tissue morphology; Pathway interactions; Perfusion; Physiological; Play; Positioning Attribute; Potassium; Property; Protein Kinase C; Receptor Activation; Regulation; Research Personnel; Resistance; Role; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; System; TRPC3 ion channel; TRPV channel; Techniques; Tissues; Translating; Vascular Endothelial Cell; Vascular Smooth Muscle; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Vasomotor; Work; arteriole; base; blood flow measurement; brain circulation; cGMP-dependent protein kinase Ibeta; capillary; capsaicin receptor; cerebral artery; cerebrovascular; expression cloning; in vivo; knowledge base; large-conductance calcium-activated potassium channels; member; novel; pressure; programs; protein expression; receptor; relating to nervous system; research study; resistance mechanism; response; vasoconstriction

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 nativeTRPCSchannels 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 hyyperpolarizing 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.

这项建议的主要目的是阐明几种新的介体的功能意义和 参与调节细胞内钙离子和脑动脉收缩的机制。通过他们的 收缩和扩张活动，大脑动脉紧密调节血流和毛细血管灌流压 在维持正常大脑功能的范围内。我们发现，暂住者的成员 受体电位(Trp)超家族离子通道存在于脑动脉中，这些通道 在脑血管功能中发挥新的、特定的和多样的作用：TRPM4辅助机械转导。 (目标1)；TRPC3转导血管收缩受体反应(目标2)；TRPV4在 血管内皮细胞/平滑肌通讯(目标3)。我们建议阐明这些特性 不同的Trp通道在脑血管系统中的作用，并确定它们的血管调节作用。特定目标 1：定义TRPM4通道的属性、信号耦合机制和独特的功能角色 大脑动脉。这些实验将揭示天然TRPM4通道的生物物理特性。 血管平滑肌，确定它们可能的机械敏感性，并考虑它们在体内的作用 功能性。特定目标2：阐明天然TRPCS通道在激动剂中的作用和调节 诱导Ca~(2+)内流和脑血管收缩。这些实验将证明， TRPC3通道作为受体操纵型阳离子通道在血管平滑肌中的作用 控制血管TRPC3活性的机制。具体目标3：界定和区分 TRPV4通道在脑动脉中的作用我们的初步数据显示了一个新的和意想不到的角色 TRPV4通道在内皮依赖性血管扩张活性中的作用 超极化因子、TRPV4通道和局部钙释放事件(钙火花)。在《目标3》中，我们将 揭示这些反应涉及的具体机制。使用多个最先进的 技术(膜电位、细胞内钙离子、直径、离子通道记录、活体血流 测量、基因沉默)以及从分子到整体的独特方法组合 动物将提供色氨酸通道在脑循环中的作用的全面观察，并表明 可用于纠正脑血流病理变化的药物的新靶点。