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 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. While rapamycin analogs are efficacious drug-eluting stent agents, the risk of late-stent thrombosis and subsequent need for long term antiplatelet therapy still complicates their use. Our previous studies have revealed that the mTORC1 inhibitor, rapamycin, promotes VSMC differentiation, revealing cell type-specific transcription as a novel function of the mTORC1 pathway. Moreover, we implicated feedback activation of Akt2 as critical for rapamycin-induced differentiation. We have discovered distinct roles for Akt1 and Akt2 in the response to vascular injury. We have also identified TET2 and LMO7 as novel mTORC1-regulated proteins that modulate VSMC phenotype. Based upon these exciting Preliminary Results we will address the overall hypothesis that the mTORC1 pathway governs VSMC phenotype and response to injury through epigenetic (TET2) and transcriptional (LMO7) regulation, and that Akt isoforms play distinct roles in the pathology of restenosis and therapeutic response to rapamycin.
In Specific Aim 1, we will determine the role of TET2 in VSMC phenotypic modulation and how it is regulated by rapamycin.
In Specific Aim 2, we will determine the role of LMO7 in rapamycin- induced VSMC differentiation in vitro and in response to injury in vivo.
In Specific Aim 3, we will determine the differential roles of Akt1 and Akt2 in injury response in vascular tissues. If our goals are achieved, we will have identified key regulatory elements in 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 and to failure of the procedures (angioplasty/stenting) that restore blood flow through atherosclerotic vessels. Delivering the drug rapamycin on stents during angioplasty very effectively prevents VSMC overgrowth. Our goal is to understand why VSMC grow excessively and how rapamycin regulates this process, in order to develop better and safer agents for prevention and therapy for other cardiovascular diseases, including atherosclerosis and transplant vasculopathy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL091013-10
Application #
9319786
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Reid, Diane M
Project Start
2008-04-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2019-07-31
Support Year
10
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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 :
Bauer, Ashley J; Martin, Kathleen A (2017) Coordinating Regulation of Gene Expression in Cardiovascular Disease: Interactions between Chromatin Modifiers and Transcription Factors. Front Cardiovasc Med 4:19
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
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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