INTERCELLULAR COMMUNICATION IN MICROVESSELS

微血管中的细胞间通讯

• 批准号: 2857841
• 负责人: BRIAN R DULING
• 金额: $ 26.36万
• 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 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2857841
• 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.

小动脉壁内的细胞细胞信号传导提供了至关重要的联系 将单个血管平滑肌和内皮细胞团结成一个 功能性抗性容器，可以作为一部分运行 微循环。化学信号传导（例如EDRF），肌原理， 流量依赖性扩张和导致的血管舒缩反应都是 涉及。这些过程不仅可以统一活动 单个单元格，但也要协调系列和平行元素 脉管系统以确保血流的均匀分布 在各个器官中和内部的细胞和分子碱基 进行的血管舒缩响应是对任何的研究 综合机制，我们的实验室已经进行了 旨在纠正此赤字的多学科计划， 提供有关有关的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。细胞是什么 导致传导的事件，以及涉及的途径 传导？我们的工具包括：体外和体内全细胞电气电气 除了电压敏感染料外，从微孔记录 测量血管平滑肌的膜电位和 内皮细胞，钙敏感染料以监测Ca ++信号传导，染料 注射痕量细胞连通性，免疫组织化学以定义 容器壁中连通性的解剖途径，原位 杂交确定连接蛋白的原始细胞（GAP 连接）。我们建议将这些工具与细胞结合使用，并 受体特定激动剂，间隙连接器和反义 寡核苷酸测试六个关键假设。 l。膜电位的变化是必要的，并且足够 引起的血管舒缩反应的信号。 2。纵向CA + +或其他第二使者的纵向扩散贡献 进行纵向交流。 3。平滑肌或内皮可以参与a。）启动， 和b。）进行响应。 4。毛细管内皮是一种将毛细管统一的传导途径 和小动物。 5。间隙连接提供同性细胞和杂细胞途径 用于传导。 6。小动物壁中的细胞间传导系统在下面 生理控制。