This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cells of the cardiovascular system are continuously exposed to the effects of mechanical forces such as stretching and fluid shear stress. These forces, which are created by the pulsatile nature of blood flow when the heart contracts and relaxes, have a marked influence on cell structure and function. The adaptations of these cells, which include enhanced growth and migration, seem to be important in the pathological conditions that accompany cardiovascular diseases such as atherosclerosis and hypertension. Cardiovascular disease remains a major cause of morbidity and mortality in the US and the economic and human costs associated with pathologies such as atherosclerosis, hypertension and restenosis are enormous. This has resulted in an intense research interest in the mechanisms which regulate contraction, migraton and growth of vascular smooth muscle cell (VSMC). While it is now clear that mechanical forces imposed on VSMC in the vessel wall are important factors in the initiation and progression of these changes, the molecular mechanisms involved in these adaptations are not fully understood. In addition, it is now clear that the basic mechanism of smooth muscle contraction can only be explained in light of actin remodeling. However, the exact nature of cytoskeletal reorganization and the mechanisms regulating these changes are not well known. The main goal of this project to is to elucidate the acute response in cytoskeletal reorganization and intracellular signaling and during mechanical stress of VSMC. Utilizing molecular approaches combined with fluorescence microscopy, and relying on the precise changes in cell orientation and actin cytoskeletal reorganization as endpoints for quantitative assessment of responsiveness to mechanical strain we will evaluate the role of various cytoskeletal structures on the response of VSMC to stretch, make a systematic determination of effects of various types of mechanical stress on activation of cell signaling molecules, and evaluate the effects of resveratrol, a purported cardioprotective molecule for its potential effects on stretch-induced cell signaling and receptor mediated cellular hypertrophy. The use of pharmacologic and molecular techniques to stabilize, destabilize or downregulate specific cytoskeletal components is expected to provide clear answers concerning the role of specific components in mechanotransduction and the cell orientation response. The inhibition or downregulation of specific signaling proteins is expected to provide information concerning pathways regulating mechanosensing and transduction. The knowledge gained may be useful in the development of therapeutic agents regulating mechanotransduction mechanisms contributing to cardiovascular pathologies.
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