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Kathleen Martin, PhD

Professor of Medicine (Cardiovascular Medicine) and Pharmacology; Co-Director, Yale Cardiovascular Research Center (YCVRC)

Contact Information

Kathleen Martin, PhD

Mailing Address

  • Cardiovascular Medicine

    Section of Cardiovascular Medicine, PO Box 208017

    New Haven, CT 06520-8017

    United States

The Martin Lab

Research Summary

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 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. We are currently emplying genome-wide epigenetic methods to investigate mechanisms by which TET2 and other epigenetic regulators coordinately remodel chromatin to allow for profound VSMC plasticity.


Coauthors

Research Interests

Cardiology; Cardiovascular Diseases; Pharmacology; Vascular Diseases; Signal Transduction

Research Image

Aorta with SM22a-cre/mTmG lineage tracing showing GFP+ medial smooth muscle layers as well as GFP+ perivascular adipocytes. Blue (DAPI) marks cell nuclei.

Selected Publications

  • Targeting smooth muscle cell phenotypic switching in vascular diseaseJVS-Vascular Science 2021;2:79-94.
  • Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation.Gu SX, Tyagi T, Jain K, Gu VW, Lee SH, Hwa JM, Kwan JM, Krause DS, Lee AI, Halene S, Martin KA, Chun HJ, Hwa J. Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation. Nature Reviews. Cardiology 2021, 18: 194-209. PMID: 33214651, PMCID: PMC7675396, DOI: 10.1038/s41569-020-00469-1.
  • Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation.Zeng Z, Xia L, Fan S, Zheng J, Qin J, Fan X, Liu Y, Tao J, Liu Y, Li K, Ling Z, Bu Y, Martin KA, Hwa J, Liu R, Tang WH. Circular RNA CircMAP3K5 Acts as a MicroRNA-22-3p Sponge to Promote Resolution of Intimal Hyperplasia Via TET2-Mediated Smooth Muscle Cell Differentiation. Circulation 2021, 143: 354-371. PMID: 33207953, DOI: 10.1161/CIRCULATIONAHA.120.049715.
  • TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy.Ostriker AC, Xie Y, Chakraborty R, Sizer AJ, Bai Y, Ding M, Song WL, Huttner A, Hwa J, Martin KA. TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy. Circulation 2021, 144: 455-470. PMID: 34111946, PMCID: PMC8643133, DOI: 10.1161/CIRCULATIONAHA.120.050553.
  • TCF21: Flipping the Phenotypic Switch in SMC.Xie Y, Martin KA. TCF21: Flipping the Phenotypic Switch in SMC. Circulation Research 2020, 126: 530-532. PMID: 32078454, PMCID: PMC7041869, DOI: 10.1161/CIRCRESAHA.120.316533.
  • Technical Feasibility of a Murine Model of Sleeve Gastrectomy with Ileal Transposition.Ying LD, Breuer GA, Hubbard MO, Nadzam GS, Hwa J, Martin KA. Technical Feasibility of a Murine Model of Sleeve Gastrectomy with Ileal Transposition. Obesity Surgery 2019, 29: 593-600. PMID: 30353248, PMCID: PMC6365182, DOI: 10.1007/s11695-018-3555-7.
  • LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis.Xie Y, Ostriker AC, Jin Y, Hu H, Sizer AJ, Peng G, Morris AH, Ryu C, Herzog EL, Kyriakides T, Zhao H, Dardik A, Yu J, Hwa J, Martin KA. LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis. Circulation 2019, 139: 679-693. PMID: 30586711, PMCID: PMC6371979, DOI: 10.1161/CIRCULATIONAHA.118.034615.
  • TCF7L2 (Transcription Factor 7-Like 2) Regulation of GATA6 (GATA-Binding Protein 6)-Dependent and -Independent Vascular Smooth Muscle Cell Plasticity and Intimal Hyperplasia.Srivastava R, Rolyan H, Xie Y, Li N, Bhat N, Hong L, Esteghamat F, Adeniran A, Geirsson A, Zhang J, Ge G, Nobrega M, Martin KA, Mani A. TCF7L2 (Transcription Factor 7-Like 2) Regulation of GATA6 (GATA-Binding Protein 6)-Dependent and -Independent Vascular Smooth Muscle Cell Plasticity and Intimal Hyperplasia. Arteriosclerosis, Thrombosis, And Vascular Biology 2019, 39: 250-262. PMID: 30567484, PMCID: PMC6365015, DOI: 10.1161/ATVBAHA.118.311830.
  • Promoters to Study Vascular Smooth Muscle.Chakraborty R, Saddouk FZ, Carrao AC, Krause DS, Greif DM, Martin KA. Promoters to Study Vascular Smooth Muscle. Arteriosclerosis, Thrombosis, And Vascular Biology 2019, 39: 603-612. PMID: 30727757, PMCID: PMC6527360, DOI: 10.1161/ATVBAHA.119.312449.
  • 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. Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response. Arteriosclerosis, Thrombosis, And Vascular Biology 2017, 37: 2311-2321. PMID: 29025710, PMCID: PMC5699966, DOI: 10.1161/ATVBAHA.117.310053.
  • 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. PMID: 28104796, PMCID: PMC5542057, DOI: 10.1126/science.aag1381.
  • 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. PMID: 28428957, PMCID: PMC5382160, DOI: 10.3389/fcvm.2017.00019.
  • 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. PMID: 24937434, PMCID: PMC4552189, DOI: 10.1016/j.bbagrm.2014.06.004.
  • 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. PMID: 25969542, PMCID: PMC4560350, DOI: 10.1126/scisignal.2005482.
  • 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. PMID: 24077167, PMCID: PMC3899790, DOI: 10.1161/CIRCULATIONAHA.113.002887.
  • 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. PMID: 19033666, PMCID: PMC2582928, DOI: 10.1172/JCI33800.
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