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Signaling Mechanisms in Myogenic Tone of Skeletal Muscle Arterioles: Role of BKCa

骨骼肌小动脉肌源性张力的信号机制：BKCa 的作用

基本信息

批准号：
8296176
负责人：
Michael A HILL
金额：
$ 36.99万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8296176
关键词：
Affect Animals Appearance Arteries Behavior Biochemical Blood Vessels Blood flow Caliber Caveolae Cells Cerebrum Characteristics Complement Complex Coupling Cyclic GMP Cyclic GMP-Dependent Protein Kinases Data Diabetes Mellitus Drug Delivery Systems Elements Endothelium Endothelium-Dependent Relaxing Factors Feedback Genes Goals Health Heterogeneity Homeostasis Hyperglycemia Hypertension In Situ In Vitro Ion Channel Knowledge Laboratories Location Measures Mediating Mediator of activation protein Membrane Membrane Potentials Messenger RNA Metabolic Microcirculation Molecular Peripheral Resistance Phosphorylation Physiological Post-Translational Protein Processing Potassium Channel Preparation Probability Property Protein Kinase Proteins RNA Splicing Rattus Regulation Relative (related person)Reliance Research Personnel Resistance Rest Role Second Messenger Systems Signal Transduction Site Skeletal Muscle Small Interfering RNA Smooth Muscle Smooth Muscle Myocytes Stimulus Testing Therapeutic Tissues Variant Vascular Diseases Vascular Smooth Muscle Vascular resistance Vasodilation Vasodilator Agents Work arteriole base caveolin 1 cerebral artery constriction cremaster muscle density design hemodynamics iberiotoxin improved inhibitor/antagonist insight mRNA Expression pressure prevent regional difference research study vasoconstriction voltage

项目摘要

DESCRIPTION (provided by applicant): Pressure-induced (myogenic) vasoconstriction is key to setting of peripheral resistance and autoregulation of blood flow. Myogenic constriction depends on smooth muscle (SM) membrane depolarization and voltage- dependent Ca2+-influx. Although myogenic responsiveness is an inherent property of arteriolar SM, it is modulated by hyperpolarizing and vasodilator influences. An important mediator of a number of vasodilator stimuli in SM is the Ca2+-sensitive large-conductance K+ ion channel (BKCa). Activation of BKCa by depolarization and increased intracellular [Ca2+] has been proposed to serve as a 'feedback' inhibitor, preventing excessive myogenic constriction of arterioles as intralumenal pressure increases. This hypothesis is largely based on studies performed in small cerebral arteries, however our work does not support an identical role for BKCa in regulating myogenic tone of skeletal muscle arterioles, which are a major contributor to peripheral resistance. Interestingly, our studies suggest a fundamental difference between skeletal muscle arterioles and small cerebral arteries in the relationship between SM membrane potential and pressure-induced constriction suggesting that in skeletal muscle vessels BKCa activation may be minimized to allow sustained vasoconstriction under resting conditions. The overall goals of the studies in this proposal are to define the physiological role and mechanisms of regulation for BKCa in arteriolar SM of skeletal muscle. Control of BKCa is complex with regulation occurring at the molecular and post-translational levels as well as by its cellular location with respect to other signaling-related molecules. This complexity of regulation provides extensive opportunity for tissue-specific heterogeneity where channel behavior is matched to local tissue requirements. Thus, our overall hypothesis is that BKCa is differentially regulated in vascular SM from cerebral and skeletal muscle. Further, such regional differences in regulation of BKCa allow for local control of hemodynamics to be appropriately matched to tissue function. Using a combination of molecular, cellular and electrophysiological approaches, in skeletal muscle and cerebral vascular preparations, the proposed studies aim to: 1. examine subunit composition and expression of BKCa; 2. test the role of BKCa subunits in modulating myogenic constriction using an siRNA knockdown approach; 3. define mechanisms of BKCa regulation in isolated SM cells with emphasis on Ca2+ and voltage sensitivity; modulation by cGMP/cGMP-dependent protein kinase; 4. test the role of BKCa in modulating myogenic tone of isolated vessels, focusing on both feedback-modulation of tone and the sensitivity of the BKCa channel to cGMP/cGMP- dependent protein kinase and vasodilator mechanisms activating this second messenger system. Understanding tissue-specific mechanisms by which BKCa function is regulated will impact on design and utilization of channel modulators developed as therapeutic measures for treatment of vascular diseases. PUBLIC HEALTH RELEVANCE: This study will improve our knowledge of how small arteries can vary their diameters and thus control local blood flow. Importantly, the data obtained will also contribute to identifying biochemical sites that may be altered in pathophysiological situations. Thus the potential exists for the identification of steps in cellular signaling that may ultimately be used for the targeting of pharmacological therapies.

描述（由申请人提供）：压力诱导的（肌源性）血管收缩是外周阻力设定和血流自动调节的关键。肌源性收缩依赖于平滑肌（SM）膜去极化和电压依赖性Ca ~（2+）内流。虽然肌源性反应是小动脉SM的固有特性，但它受到超极化和血管扩张剂影响的调节。SM中许多血管舒张刺激的重要介质是Ca 2+敏感性大电导K+离子通道（BKCa）。通过去极化和增加细胞内[Ca 2 +]激活BKCa已被提议用作“反馈”抑制剂，防止随着腔内压力增加而引起的小动脉过度肌源性收缩。该假设主要基于在小脑动脉中进行的研究，然而，我们的工作不支持BKCa在调节骨骼肌小动脉肌源性张力中的相同作用，骨骼肌小动脉是外周阻力的主要贡献者。有趣的是，我们的研究表明，在SM膜电位和压力诱导的收缩之间的关系中，骨骼肌小动脉和脑小动脉之间存在根本性差异，这表明在骨骼肌血管中，BKCa激活可能会最小化，以允许在静息条件下持续的血管收缩。本研究的总体目标是确定骨骼肌小动脉SM中BKCa的生理作用和调节机制。BKCa的控制是复杂的，在分子和翻译后水平上以及通过其相对于其他信号相关分子的细胞位置进行调节。调节的这种复杂性为组织特异性异质性提供了广泛的机会，其中通道行为与局部组织要求相匹配。因此，我们的总体假设是，BKCa差异调节血管SM从大脑和骨骼肌。此外，BKCa调节的这种区域差异允许局部控制血流动力学以适当地匹配组织功能。使用分子，细胞和电生理学方法的组合，在骨骼肌和脑血管的准备，拟议的研究旨在：1。检测BKCa的亚基组成和表达; 2.使用siRNA敲低方法测试BKCa亚基在调节肌源性收缩中的作用; 3.确定分离的SM细胞中BKCa调节的机制，重点是Ca 2+和电压敏感性; cGMP/cGMP依赖性蛋白激酶的调节; 4.测试BKCa在调节离体血管的肌源性张力中的作用，重点是张力的反馈调节和BKCa通道对cGMP/cGMP依赖性蛋白激酶和激活该第二信使系统的血管舒张剂机制的敏感性。了解BKCa功能调节的组织特异性机制将影响作为治疗血管疾病的治疗措施开发的通道调节剂的设计和利用。公共卫生相关性：这项研究将提高我们对小动脉如何改变其直径从而控制局部血流的认识。重要的是，所获得的数据也将有助于确定在病理生理情况下可能改变的生化位点。因此，有可能识别细胞信号传导中的步骤，这些步骤最终可能用于靶向药理学治疗。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries: Impaired Trafficking of RGS5 in Hypertension.

DOI：
10.1161/hypertensionaha.117.09757
发表时间：
2017-12
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
0
作者：
Hong K;Li M;Nourian Z;Meininger GA;Hill MA
通讯作者：
Hill MA

Development of an image-based system for measurement of membrane potential, intracellular Ca(2+) and contraction in arteriolar smooth muscle cells.

开发基于图像的系统，用于测量膜电位、细胞内 Ca(2) 和小动脉平滑肌细胞的收缩。

DOI：
10.1111/j.1549-8719.2010.00059.x
发表时间：
2010
期刊：
Microcirculation (New York, N.Y. : 1994)
影响因子：
0
作者：
Ella,SrikanthR;Yang,Yan;Clifford,PhilipS;Gulia,Jyoti;Dora,KimA;Meininger,GeraldA;Davis,MichaelJ;Hill,MichaelA
通讯作者：
Hill,MichaelA

Measurement of changes in endothelial and smooth muscle Ca²⁺ in pressurized arteries.

测量加压动脉中内皮和平滑肌 Ca2+ 的变化。