Epigenetic control of vascular smooth muscle in cardiovascular disease

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DESCRIPTION (provided by applicant): Vascular smooth muscle cells (VSMC) exhibit a remarkable plasticity that allows for reversible differentiation and de-differentiation. This propety is distinct from skeletal or cardiac myocytes, which undergo terminal differentiation. Smooth muscle plasticity is important in normal development, growth, and wound healing, but also contributes to pathologies including atherosclerosis, intimal hyperplasia, hypertension, and transplant arteriosclerosis. Because VSMC exhibit this unique plasticity, we hypothesized that regulatory mechanisms found in other types of stem cells might also be involved in VSMC phenotypic modulation. Indeed, our preliminary data demonstrate that de-differentiated VSMC express multiple stem cell genes, including Oct4, Nanog, and KLF4. As the TET (ten-eleven translocation) family of chromatin-modifying proteins has recently been implicated as essential regulators of pluripotency in embryonic and hematopoietic stem cells, we investigated the roles of TET proteins in VSMC. Our preliminary data reveal that TET2 is expressed at high levels in VSMC, and is induced by differentiating agents but repressed by PDGF-BB. We find that TET2 is necessary and sufficient for SMC differentiation, where TET2 associates with contractile gene promoters and increases accessibility, but represses chromatin at stem cell gene promoters. We further found that TET2 is expressed at high levels in normal vessels, but markedly downregulated in disease states, including human atherosclerosis and intimal hyperplasia in mice. Importantly, TET2 overexpression rescues intimal hyperplasia post-arterial injury. We hypothesize that TET2 is a novel epigenetic master regulator of VSMC phenotype. We believe we have uncovered a fundamental new mechanism that is the basis for smooth muscle plasticity. As such, this work has important implications for multiple vascular diseases. In the following specific aims, we propose to address mechanisms of action of TET2, and determine the role of TET2 in vascular disease models. In Specific Aim 1, we will use cutting edge methods to determine the epigenetic mechanisms by which TET2 regulates methylation and gene expression at contractile and stem cell promoters. In Specific Aim 2, we will use mouse models to determine the role of TET2 in the pathogenesis of cardiovascular diseases, including atherosclerosis, intimal hyperplasia, and graft arteriosclerosis. Because we have found that epigenetic regulation by TET2 lies at the apex of VSMC phenotypic modulation, controlling other known mediators such as myocardin, SRF, and KLF4, we propose that understanding the mechanisms of TET2 action at the cellular and disease level will generate new therapeutic approaches for treatment and prevention of cardiovascular disease.