This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Mechanical forces imposed on vascular smooth muscle (VSM) are important modulators of cell structure and function. Much of the interest in mechanically-induced responses of cultured cells stems from their similarity to processes leading to pathological conditions. These responses which include cell migration and reorganization of the cytoskeleton are believed to be mediated through mechanisms involving mechanosensing and transduction originating at the cytoskeleton- extracellular substrate interface. It is further recognized that organizational changes in the actin cytoskeleton are essential for effective contraction, mechanotransduction and signaling in different cell types. However, the exact nature of cytoskeletal reorganization has not been studied and the mechanisms regulating these changes are largely unknown in VSM. We have found that in response to unidirectional stretch, A7r5 smooth muscle cells reorient their position is manner that is dependent on the degree of stretch. Thus, this model provides an endpoint for quantitative assessment of responsiveness to mechanical strain. Utilizing molecular approaches combined with confocal microscopy we will evaluate the role of actin and microtubular components of the cytoskeleton in the cells? response to stretch, determine the role of the mitogen-activated protein kinase signal transduction pathways in the stretch response, and determine the effect of stretch-induced cytoskeletal reorganization on expression of key signal transduction and focal adhesion proteins. The long-term objectives of this project are to understand the role that the cytoskeleton plays in mechanoresponsiveness and to identify changes in expression and regulation of proteins regulating the response, as well as to understand the mechanisms underlying sensing and transduction of mechanical signals. The knowledge gained may be useful in the development of therapeutic agents regulating mechanotransduction mechanisms contributing to cardiovascular pathologies.
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