INTERCELLULAR COMMUNICATION IN MICROVESSELS

微血管中的细胞间通讯

• 批准号: 2231173
• 负责人: BRIAN R DULING
• 金额: $ 28.22万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2231173
• 关键词: antisense nucleic acid; arterioles; calcium; cardiovascular function; cardiovascular pharmacology; cell cell interaction; dyes; electrophysiology; gap junctions; hamsters; immunochemistry; in situ hybridization; membrane potentials; microelectrodes; oligonucleotides; second messengers; vascular endothelium; vascular smooth muscle; vasomotion

Cell-cell signaling within the arteriolar wall provides a vital link uniting individual vascular smooth muscle and endothelial cells into a functional resistance vessel which can operate as a part of the microcirculation. Chemical signaling (e.g. EDRF), the myogenic mechanism, flow dependent dilation and the conducted vasomotor response are all involved. These processes serve not only to unify the activities of the individual cells, but also to coordinate the series and parallel elements of the vasculature so as to assure the uniform distribution of blood flow among and within the various organs The cellular and molecular bases of the conducted vasomotor response have been the least investigated of any of the integrative mechanisms, and our laboratory has undertaken a multidisciplinary program aimed at rectifying this deficit, and in providing insights into the basic physiology and pathophysiology of the vascular wall. Two broad questions are addressed. What are the cellular events leading to conduction, and what are the pathways involved in conduction? Our tools include: in vitro and in vivo whole-cell electrical recording from micropipettes in addition to voltage sensitive dyes for measurement of membrane potential of vascular smooth muscle and endothelial cells, calcium sensitive dyes to monitor Ca++ signaling, dye injection to trace cellular connectivity, immunohistochemistry to define the anatomical pathways of connectivity in the vessel wall, and in situ hybridization to determine the cells of origin for connexin proteins (gap junctions). We propose to use these tools in combination with cell and receptor specific agonists, gap junction uncouplers, and antisense oligonucleotides to test six critical hypotheses. l. A change in membrane potential is the necessary and the sufficient signal for conducted vasomotor response. 2. Longitudinal diffusion of Ca+ + or other second messenger contributes to longitudinal communication. 3. Either smooth muscle or endothelium may participate in a.) initiating, and b.) conducting the response. 4. The capillary endothelium is a conduction pathway uniting capillaries and arterioles. 5. The gap junctions provide both homocellular and heterocellular pathways for conduction. 6. The intercellular conduction system in the arteriolar wall is under physiological control.

动脉壁内的细胞间信号传导提供了重要的联系 将单个血管平滑肌和内皮细胞结合成一个 功能性阻力容器，可以作为 微循环。化学信号传导（例如 EDRF）、生肌机制、 流量依赖性扩张和传导的血管舒缩反应都是 涉及。这些过程不仅有助于统一各组织的活动 单个电池，还协调串联和并联元件 血管系统，以保证血流的均匀分布 各个器官之间和内部的细胞和分子基础 所进行的血管舒缩反应是所有研究中研究最少的 的综合机制，我们的实验室已经开展了 旨在纠正这一缺陷的多学科计划 提供对基本生理学和病理生理学的见解 血管壁。解决了两个广泛的问题。什么是蜂窝 导致传导的事件以及涉及的途径是什么 传导？我们的工具包括：体外和体内全细胞电学 除了电压敏感染料之外，还可以从微量移液器进行记录 血管平滑肌膜电位的测量和 内皮细胞、用于监测 Ca++ 信号传导的钙敏感染料、染料 注射来追踪细胞连接性，免疫组织化学来定义 血管壁和原位连接的解剖通路 杂交以确定连接蛋白的起源细胞（间隙 路口）。我们建议将这些工具与细胞和 受体特异性激动剂、间隙连接解偶联剂和反义 寡核苷酸来测试六个关键假设。 湖膜电位的变化是必要且充分的 传导血管舒缩反应的信号。 2. Ca++或其他第二信使的纵向扩散有贡献 进行纵向沟通。 3. 平滑肌或内皮细胞可以参与 a.) 启动， b.) 进行响应。 4.毛细血管内皮是连接毛细血管的传导通路 和小动脉。 5.间隙连接提供同源和异源细胞途径 用于传导。 6、小动脉壁的细胞间传导系统处于 生理控制。