Transcriptional co-activators expand information encoded within the genome in response to developmental cues and environmental stress. Myocardin is remarkably potent transcriptional coactivator expressed exclusively in smooth muscle cells (SMCs) and cardiac myocytes. Our group and others have shown that myocardin, plays a critical role in regulating differentiation of vascular SMCs. The overall goal of the proposed studies is to elucidate the role of myocardin and two related transcriptional co-activators, MRTF-A and MRTF-B, in the embryonic and adult vasculature. During the last cycle of this award, we reported that: i) myocardin, MRTF-A and MRTF-B are expressed in distinct developmentally-regulated patterns in mesodermally- and neural crest-derived SMCs, ii) forced expression of myocardin, MRTF-A or MRTF-B in embryonic stem (ES) cells activates endogenous SMC-restricted genes, iii) mice in which the myocardin gene is ablated in neural crest-derived SMCs exhibit patent ductus arteriosus (PDA) resulting from a block in SMC differentiation, iv) myocardin-deficient primary aortic SMCs assume a synthetic phenotype, and v) MRTF-B null mice exhibit patterning defects of the cardiac outflow tract and great arteries attributable, in part, to a cell autonomous block in differentiation of neural crest-derived SMCs. Together these studies suggest the central hypothesis that will be examined in the proposed studies: Myocardin related transcription factors (MRTFs) transduce cell autonomous and non-cell autonomous signals required for SMC differentiation, vascular patterning and maintenance and adaptation of the vasculature during postnatal development.
The specific aims are to examine: 1) the cell autonomous function(s) of myocardin, MRTF-A and MRTF-B that promote SMC differentiation and the contractile SMC phenotype;2) the role of MRTF-A and MRTF-B in differentiation of neural crest-derived SMCs and patterning of the cardiac outflow tract and great arteries;and 3) myocardin null and conditional mutant mice to elucidate the function of myocardin during embryonic angiogenesis and in maintenance and adaptation of the postnatal vasculature. The experimental strategies deployed emphasize the translation of molecular and cellular data to the intact vascular system utilizing genetically engineered mice. At a basic level, these studies will provide new insights into the molecular programs regulating smooth muscle cell differentiation and morphogenetic patterning of the vasculature. Moreover, these studies are directly relevant to understanding the molecular and genetic basis of vascular proliferative syndromes, congenital heart disease and diseases of the aorta.

Public Health Relevance

Compelling evidence suggests that myocardin related transcription factors (MRTFs) play critical roles in regulating development of the cardiovascular system and maintenance of cardiovascular homeostasis. The proposed studies examine the molecular mechanisms regulating activity of MRTFs during embryonic and postnatal development. These studies are directly relevant to understanding vascular proliferative syndromes including atherosclerosis, common forms of congenital heart disease and aortic diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Gao, Yunling
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Mughal, Wajihah; Martens, Matthew; Field, Jared et al. (2018) Myocardin regulates mitochondrial calcium homeostasis and prevents permeability transition. Cell Death Differ 25:1732-1748
Nguyen, Anh T; Gomez, Delphine; Bell, Robert D et al. (2013) Smooth muscle cell plasticity: fact or fiction? Circ Res 112:17-22
Li, Jian; Bowens, Nina; Cheng, Lan et al. (2012) Myocardin-like protein 2 regulates TGF? signaling in embryonic stem cells and the developing vasculature. Development 139:3531-42
Huang, Jianhe; Parmacek, Michael S (2012) Modulation of smooth muscle cell phenotype: the other side of the story. Circ Res 111:659-61
Rong, Li; Liu, Jie; Qi, Yanmei et al. (2012) GATA-6 promotes cell survival by up-regulating BMP-2 expression during embryonic stem cell differentiation. Mol Biol Cell 23:3754-63
Huang, Jianhe; Elicker, John; Bowens, Nina et al. (2012) Myocardin regulates BMP10 expression and is required for heart development. J Clin Invest 122:3678-91
Rader, Daniel J; Parmacek, Michael S (2012) Secreted miRNAs suppress atherogenesis. Nat Cell Biol 14:233-5
Shen, Dongxiao; Li, Jian; Lepore, John J et al. (2011) Aortic aneurysm generation in mice with targeted deletion of integrin-linked kinase in vascular smooth muscle cells. Circ Res 109:616-28
Parmacek, Michael S (2010) Myocardin-related transcription factor-A: mending a broken heart. Circ Res 107:168-70