Vascular smooth muscle cells (VSMC) in the blood vessel wall normally exhibit a differentiated, contractile phenotype. Their primary functions include modulating vascular tone through their contractile state and synthesizing the extracellular matrix scaffold that serves as a structural component of the blood vessel. In response to arterial damage or hypercholesterolemia, VSMC undergo a phenotypic change by down- regulating contractile protein expression, proliferate, and migrate leading to neointima formation and blood vessel narrowing. This phenotypic change and subsequent vessel occlusion can cause tissue ischemia or lead to myocardial infarction. There is a clear gap in knowledge concerning the role of proteins that control these processes. Our long-term goals are to understand the transcriptional control of genes, which are up- regulated in neointimal VSMC, and the mechanisms by which their encoded proteins contribute to the progression of vascular disease. Our studies have identified a secreted protein, aortic carboxypeptidase-like protein (ACLP) that is induced in neointimal VSMC. ACLP transcription is not mediated by CArG box-serum response factor (SRF) interactions indicating that the study of ACLP regulation may elucidate novel aspects of VSMC gene regulation in vascular disease. We have generated ACLP-null mice and our preliminary results indicate that in response to femoral artery injury these mice have a smaller neointima with fewer proliferative VSMC, and VSMC isolated from these ACLP-null mice exhibit a reduced proliferative capacity. Consistent with a role for ACLP in VSMC proliferation, adenoviral overexpression of ACLP stimulates PDGF- mediated VSMC proliferation. Our central hypothesis is that ACLP is an important regulator of blood vessel neointima formation under pathological conditions. Our goals are to investigate the role of ACLP in the progression of neointima formation using ACLP-null mice in a femoral artery injury model; investigate the mechanisms by which ACLP promotes VSMC proliferation, characterize ACLP-extracellular matrix and growth factor interactions by studying VSMC in culture; and to investigate the SRF-independent regulation of ACLP expression in vitro and determine the promoter elements required for ACLP expression in neointimal VSMC in vivo using transgenic mice and vascular disease models. The proposed experiments will provide important new knowledge about the molecular mechanisms regulating VSMC proliferation. These studies on ACLP transcriptional control and function in VSMC may lead to novel treatment approaches for atherosclerosis and the prevention of restenosis after coronary bypass or angioplasty. ? ? ?
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