Vascular cell-to-cell communication during remodeling

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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.