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 translocation) 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 novel 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL118430-01A1
Application #
8630004
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Olive, Michelle
Project Start
2014-02-03
Project End
2018-01-31
Budget Start
2014-02-03
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$790,875
Indirect Cost
$315,875
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Liu, Renjing; Leslie, Kristen L; Martin, Kathleen A (2015) Epigenetic regulation of smooth muscle cell plasticity. Biochim Biophys Acta 1849:448-53
Martin, Kathleen A; Hirschi, Karen K (2014) The magic touch: endothelial cells muscle-up adipose. Circ Res 115:752-4