Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Arterial hypertension produces structural changes in the arterial wall which accelerates the atherogenic process. These responses, which include growth and remodeling of smooth muscle cells (VSMC) are mediated, at least in part, through specific circulating factors whose production are altered in association with hypertension. In addition mechanical forces can directly influence VSMC growth and phenotype by activating distinct signaling pathways. Application of cyclic mechanical strain to VSMC in vitro and in vivo leads to activation of the extracellular-regulated kinases (ERKs) and the c-Jun amino terminal kinases (JNKs), members of the mitogen-activated protein kinase (MAP kinase) family of kinases. These enzymes have been shown to modulate cell proliferation and differentiation through phosphorylation of specific transcription factors and intracellular enzymes. The normal and pathophysiologic responses of VSMC will be a consequence of the interplay between signals generated in response to circulating factors, extracellular matrix components, and mechanical strain. The goal of this proposal is to investigate the interaction between mechanical strain, extracellular matrix and circulating factors in controlling the growth and phenotypic state of cultured VSMC. We hypothesize that integration of signals from these stimuli through the MAP kinase family will play an important role in the physiologic responses of these cells. Furthermore, we propose to examine whether cells derived from a genetic model of essential hypertension, the spontaneously hypertensive rat (SHR) show abnormalities in their responsiveness to mechanical strain, resulting in enhanced growth properties. Specific Aim 1 will examine changes in growth and muscle gene expression of VSMC in response to cyclic mechanical strain. The effect of cyclic mechanical strain on the growth response of VSMC will assessed in the absence and presence of known stimulators of growth. Interactions of mechanical strain with extracellular matrix will be examined by growing cells on extracellular matrices of defined composition. Changes in expression of muscle-specific markers (SM-a-actin and SM-myosin (SM1,2) will be assessed. Specific Aim 2 will define the molecular pathways leading to regulation of all three branches of the MAP kinase family in response to cyclic mechanical strain, and determine the role of this pathway in the physiologic responses of VSMC. Upstream activators of MAP kinase members will be identified. The effect of pharmacological and molecular inhibitors of these pathways will be examined. Specific Aim 3 will compare the effects of mechanical strain on aortic SMC isolated from SHR and WKY rats to determine if abnormal responses to strain mediate the altered growth properties of these cells.
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