Regulation of VSMC phenotype remains a key unanswered question in vascular smooth muscle cell (VSMC) biology. VSMC retain a remarkable plasticity to de-differentiate and re-enter the cell cycle allowing for growth and healing. However, such plasticity can also contribute to severe vascular pathologies, including restenosis, graft failure, atherosclerosis, and transplant vasculopathy. Remarkably, despite intense study, the process regulating VSMC plasticity is largely unknown with few therapies successfully targeting this process. With the growing numbers of patients suffering from vascular disease the discovery of novel targets is urgently warranted. We have made the exciting discovery that de-differentiated VSMC express genes associated with stem cell pluripotency, including Sox2, Oct4, Nanog, and KLF4. We propose that these stem cell-associated genes account for the unique plasticity of mature VSMC. Recent groundbreaking studies have identified the TET (ten-eleven translocations) family of chromatin modifying proteins as key mediators of pluripotency in embryonic and hematopoietic stem cells. Our Preliminary Results implicate TET2 as an epigenetic master regulator of VSMC phenotype. Importantly, we find that TET2 inhibits expression of stem cell-associated genes and classic markers of the de-differentiated phenotype. We previously discovered that the mTORC1 inhibitor, rapamycin, promotes VSMC differentiation. We now find that rapamycin regulates TET2 expression. Remarkably, we find that TET2 also regulates miRNAs that can modulate both differentiation-specific and stem cell-associated gene expression. We hypothesize that TET2 is a master regulator of VSMC phenotype through its coordinated regulation of the promoters of contractile and stem cell-associated genes, as well as of miRNAs.
In Specific Aim 1, we will determine the role of stem cell-associated genes in VSMC phenotype.
In Specific Aim 2, we will determine the role of TET2-regulated miRNAs in VSMC phenotype.
In Specific Aim 3, we will determine whether targeting TET2 or stem cell-associated genes has therapeutic utility in in vivo models of intimal hyperplasia. If our goals are achieved, we will have identified a nove mechanism underlying VSMC plasticity. Understanding the critical mechanisms by which mTORC1 regulates VSMC phenotype will lead to improved cardiovascular therapeutics.

Public Health Relevance

Excessive growth of vascular smooth muscle cells (VSMC) contributes to atherosclerosis, as well as to failure of the procedures (angioplasty/stenting, bypass surgery) that restore blood flow through atherosclerotic vessels. Our goal is to understand why VSMC grow excessively, in order to develop better and safer agents for prevention and therapy of cardiovascular diseases. We have discovered a new pathway that alters DNA in VSMC, and may be an important target for future therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Olive, Michelle
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Ying, Lee D; Breuer, Gregory A; Hubbard, Matthew O et al. (2018) Technical Feasibility of a Murine Model of Sleeve Gastrectomy with Ileal Transposition. Obes Surg :
Sizer, Ashley J; Martin, Kathleen A (2017) Respecting boundaries: CTCF, chromatin structural organization, and heart failure. J Thorac Dis 9:4889-4892
Jin, Yu; Xie, Yi; Ostriker, Allison C et al. (2017) Opposing Actions of AKT (Protein Kinase B) Isoforms in Vascular Smooth Muscle Injury and Therapeutic Response. Arterioscler Thromb Vasc Biol 37:2311-2321
Fuster, José J; MacLauchlan, Susan; Zuriaga, María A et al. (2017) Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355:842-847
Liu, Renjing; Bauer, Ashley J; Martin, Kathleen A (2016) A New Editor of Smooth Muscle Phenotype. Circ Res 119:401-3
Ulrich, Victoria; Rotllan, Noemi; Araldi, Elisa et al. (2016) Chronic miR-29 antagonism promotes favorable plaque remodeling in atherosclerotic mice. EMBO Mol Med 8:643-53
Ostriker, Allison C; Martin, Kathleen A (2015) Bromodomain Blockade for Intimal Hyperplasia--A Good BET? EBioMedicine 2:1574-5
Xiang, Yaozu; Cheng, Jijun; Wang, Dandan et al. (2015) Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor. Blood 125:3377-87
Xie, Yi; Jin, Yu; Merenick, Bethany L et al. (2015) Phosphorylation of GATA-6 is required for vascular smooth muscle cell differentiation after mTORC1 inhibition. Sci Signal 8:ra44
Martin, Kathleen A; Mani, Mitra V; Mani, Arya (2015) New targets to treat obesity and the metabolic syndrome. Eur J Pharmacol 763:64-74

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