Research Departments & Organizations
Our overall goal is to understand how regulation of the muscular layer of blood vessels contributes to normal vessel function and to cardiovascular disease. Hyperproliferation or dysfunction in vascular smooth muscle cells contributes to atherosclerosis, hypertension, organ transplant failure, and failure of revascularization therapies such as balloon angioplasty or bypass surgery. By understanding the regulatory mechanisms of vascular smooth muscle, we aim to develop new therapies for treatment and prevention of cardiovascular diseases.
Specialized Terms: Vascular smooth muscle; Differentiation; Signal transduction; Transcription; Epigenetics
Extensive Research Description
Brief Research Summary
Our studies are aimed at understanding the molecular mechanisms that regulate vascular smooth muscle cell (SMC) phenotype. Mature SMC retain the ability to de-differentiate and re-enter the cell cycle. This is essential for such processes as angiogenesis, but also contributes to the pathogenesis of atherosclerosis, intimal hyperplasia, and restenosis.
Regulation of Vascular Smooth Muscle Phenotype: Rapamycin-eluting stents have revolutionized treatment of coronary artery disease, dramatically reducing restenosis. While highly efficacious in this localized drug delivery setting, systemic high dose rapamycin is not a viable strategy for other vascular diseases due to adverse effects. Our goal is to understand the molecular mechanisms by which rapamycin beneficially affects SMC phenotype, in order to develop novel therapeutics. Identifying the smooth muscle-specific targets of the mTOR pathway may generate new therapeutic strategies for treatment and prevention of atherosclerosis and intimal hyperplasia.
Epigentic regulation: We have recently discovered that the mTOR pathway promotes VSMC differentiation through regulation of the DNA modifying enzyme TET2. We have identified TET2 as a novel master epigenetic regulator of VSMC phenotype. Notably, TET2 promotes changes in chromatin that lead to expression of prodifferentiation genes including SRF and myocardin and contractile genes such as SM-MHC and SM-alpha actin, while concomitantly downregulating expression of de-differentiation-associated genes including KFL4.
Akt signaling: We have previously shown that rapamycin feedback signaling through Akt2 underlies its effects on VSMC phenotype in vitro. We are currently studying the effects of Akt isoforms in rapamycin therapeutic response in vivo and have uncovered exciting Akt isoform-specific effects that reveal opposing roles for these nhighly related kinases. We are also studying Akt-regulated transcription factors and cyto skeletal-associated proteins that contribute to VSMC phenotypic modulation.
Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity.
Liu R, Jin Y, Tang WH, Qin L, Zhang X, Tellides G, Hwa J, Yu J, Martin KA. Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity. Circulation 2013, 128:2047-57. 2013
Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition.
Fetalvero KM, Zhang P, Shyu M, Young BT, Hwa J, Young RC, Martin KA. Prostacyclin primes pregnant human myometrium for an enhanced contractile response in parturition. The Journal Of Clinical Investigation 2008, 118:3966-79. 2008
Rapamycin promotes vascular smooth muscle cell differentiation through insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt2 feedback signaling.
Martin KA, Merenick BL, Ding M, Fetalvero KM, Rzucidlo EM, Kozul CD, Brown DJ, Chiu HY, Shyu M, Drapeau BL, Wagner RJ, Powell RJ. Rapamycin promotes vascular smooth muscle cell differentiation through insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt2 feedback signaling. The Journal Of Biological Chemistry 2007, 282:36112-20. 2007
Phosphorylation of GATA-6 is required for vascular smooth muscle cell differentiation after mTORC1 inhibition.
Xie Y, Jin Y, Merenick BL, Ding M, Fetalvero KM, Wagner RJ, Mai A, Gleim S, Tucker DF, Birnbaum MJ, Ballif BA, Luciano AK, Sessa WC, Rzucidlo EM, Powell RJ, Hou L, Zhao H, Hwa J, Yu J, Martin KA. Phosphorylation of GATA-6 is required for vascular smooth muscle cell differentiation after mTORC1 inhibition. Science Signaling 2015, 8:ra44. 2015
Epigenetic regulation of smooth muscle cell plasticity.
Liu R, Leslie KL, Martin KA. Epigenetic regulation of smooth muscle cell plasticity. Biochimica Et Biophysica Acta 2015, 1849:448-53. 2015
Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.
Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, Wu CL, Sano S, Muralidharan S, Rius C, Vuong J, Jacob S, Muralidhar V, Robertson AA, Cooper MA, Andrés V, Hirschi KK, Martin KA, Walsh K. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science (New York, N.Y.) 2017, 355:842-847. 2017
Coordinating Regulation of Gene Expression in Cardiovascular Disease: Interactions between Chromatin Modifiers and Transcription Factors.
Bauer AJ, Martin KA. Coordinating Regulation of Gene Expression in Cardiovascular Disease: Interactions between Chromatin Modifiers and Transcription Factors. Frontiers In Cardiovascular Medicine 2017, 4:19. 2017
Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response.
Jin Y, Xie Y, Ostriker AC, Zhang X, Liu R, Lee MY, Leslie KL, Tang W, Du J, Lee SH, Wang Y, Sessa WC, Hwa J, Yu J, Martin KA Arterioscler Thromb Vasc Biol. 2017 Dec; 2017 Oct 12. PMID: 29025710 2017