Vascular cell-to-cell communication during remodeling

重塑过程中的血管细胞间通讯

• 批准号: 7012521
• 负责人: ROBIN C LOOFT-WILSON
• 金额: $ 21.02万
• 依托单位: COLLEGE OF WILLIAM AND MARY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-08 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7012521
• 关键词: biological models; capillary bed; cell cell interaction; cell growth regulation; gap junctions; genetically modified animals; green fluorescent proteins; hemodynamics; immunocytochemistry; intravital microscopy; laboratory mouse; membrane channels; polymerase chain reaction; receptor expression; shear stress; vasoconstriction; vasodilation

DESCRIPTION (provided by applicant): The overall goal of this project is to understand the role of cell-to-cell communication in vascular remodeling. Remodeling is an important process that is both beneficial (e.g., enlargement of arteries during exercise training) and pathological,(e.g., narrowing of arteries during hypertension), and it is unknown what role cell- to-cell communication plays in this process. Cell-to-cell communication occurs through gap junctions that link the interiors of neighboring cells and allows coordinated responses to stimuli. This communication is important for coordinated contraction/relaxation of arteries and vascular development, and thus is likely to be involved in the coordination of vascular cells during remodeling. The specific goal of this project is to understand the effect of altered flow on cell-to-cell communication and expression of the proteins that constitute gap junctions. Altered flow is a primary stimulus for vascular remodeling, where increased flow promotes vessel lumen enlargement and decreased flow promotes narrowing. Using a cultured vessel model, early changes (24, 48 hrs) in cell-to-cell communication (assessed by evaluating conducted vasomotor responses, and vasodilation due to endothelium-derived hyperpolarizing factor) and gap junction protein expression (assessed by immunohistochemistry and quantitative PCR) will be measured in response to decreased or increased flow through the vessel lumen, while maintaining lumen pressure and tissue environment. The effects of chronically increased flow on these parameters will also be measured in vivo in gluteus maximus muscle 8 d after ligation surgery, which promotes increased flow and remodeling in collateral arteries. Vessel function will be assessed by intravital microscopy using transgenic mice with fluorescent vessels (i.e., endothelial cells express green fluorescent protein) to effectively measure vessel diameter responses. Because vascular remodeling is an important process for allowing blood vessels to meet the metabolic demands of tissues, understanding the ability of cells to communicate during this process will provide insight into the remodeling process and response to flow. Decreased cell-to-cell communication has been linked to vascular dysfunction, which is a major component of atherosclerosis. Little is known about how vascular cell-to-cell communication is regulated, and it is important to understand how a major physical force, such as flow, affects this important vascular function.

描述（由申请人提供）：本项目的总体目标是了解细胞间通讯在血管重塑中的作用。重塑是一个重要的过程，既有益（例如，运动训练期间动脉的扩大）和病理性的，（例如，高血压期间动脉狭窄），并且细胞间通讯在该过程中起什么作用尚不清楚。细胞与细胞之间的通讯是通过缝隙连接进行的，缝隙连接将相邻细胞的内部连接起来，并允许对刺激做出协调的反应。这种通信对于动脉的协调收缩/舒张和血管发育是重要的，因此可能参与重塑期间血管细胞的协调。该项目的具体目标是了解改变流动对细胞间通讯和构成间隙连接的蛋白质表达的影响。血流改变是血管重塑的主要刺激因素，其中血流增加促进血管腔扩大，血流减少促进狭窄。使用培养的血管模型，在维持管腔压力和组织环境的同时，将测量细胞间通讯（通过评价传导的血管收缩反应和内皮源性超极化因子引起的血管舒张进行评估）和间隙连接蛋白表达（通过免疫组织化学和定量PCR评估）对通过血管管腔的流量减少或增加的响应的早期变化（24、48小时）。在结扎手术后8天，还将在体内测量慢性增加的流量对这些参数的影响，这促进了侧支动脉中的流量增加和重塑。将使用具有荧光血管的转基因小鼠（即，内皮细胞表达绿色荧光蛋白）以有效地测量血管直径响应。由于血管重塑是允许血管满足组织代谢需求的重要过程，因此了解细胞在此过程中的通信能力将提供对重塑过程和对流动的响应的见解。细胞间通讯的减少与血管功能障碍有关，血管功能障碍是动脉粥样硬化的主要组成部分。关于血管细胞间的通讯是如何调节的，我们知之甚少，重要的是要了解一个主要的物理力量，如流动，如何影响这一重要的血管功能。