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Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice
Jianhe Huang, … , Jonathan A. Epstein, Michael S. Parmacek
Jianhe Huang, … , Jonathan A. Epstein, Michael S. Parmacek
Published January 10, 2008
Citation Information: J Clin Invest. 2008;118(2):515-525. https://doi.org/10.1172/JCI33304.
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Research Article Development Article has an altmetric score of 8

Myocardin regulates expression of contractile genes in smooth muscle cells and is required for closure of the ductus arteriosus in mice

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Abstract

Myocardin (Myocd) is a potent transcriptional coactivator that has been implicated in cardiovascular development and adaptation of the cardiovascular system to hemodynamic stress. To determine the function of myocardin in the developing cardiovascular system, MyocdF/F/Wnt1-Cre+ and MyocdF/F/Pax3-Cre+ mice were generated in which the myocardin gene was selectively ablated in neural crest–derived SMCs populating the cardiac outflow tract and great arteries. Both MyocdF/F/Wnt1-Cre+ and MyocdF/F/Pax3-Cre+ mutant mice survived to birth, but died prior to postnatal day 3 from patent ductus arteriosus (PDA). Neural crest–derived SMCs populating the ductus arteriosus (DA) and great arteries exhibited a cell autonomous block in expression of myocardin-regulated genes encoding SMC-restricted contractile proteins. Moreover, Myocd-deficient vascular SMCs populating the DA exhibited ultrastructural features generally associated with the SMC synthetic, rather than contractile, phenotype. Consistent with these findings, ablation of the Myocd gene in primary aortic SMCs harvested from Myocd conditional mutant mice caused a dramatic decrease in SMC contractile protein expression. Taken together, these data demonstrate that myocardin regulates expression of genes required for the contractile phenotype in neural crest–derived SMCs and provide new insights into the molecular and genetic programs that may underlie PDA.

Authors

Jianhe Huang, Lan Cheng, Jian Li, Mary Chen, Deying Zhou, Min Min Lu, Aaron Proweller, Jonathan A. Epstein, Michael S. Parmacek

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Figure 2

Wnt1-Cre mediated recombination in neural crest–derived SMCs.

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Wnt1-Cre mediated recombination in neural crest–derived SMCs.
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(A and B) Wnt1-Cre transgenic mice were interbred with R26R mice to define pattern of Cre-mediated gene excision. (A) P2 R26R+ control mouse demonstrating normal patterning of the cardiac outflow tract and great arteries, pulmonary artery (PA), DA, ascending aorta (AAo), descending aorta (DAo), carotid arteries (CA), and subclavian artery (SC). Original magnification, ×10. (B) P2 Wnt1-Cre+/R26R+mouse demonstrating β-galactosidase expression (blue stain) in arteries populated by neural crest–derived SMCs. Original magnification, ×10. (C) Transverse section of P2 Wnt1-Cre+/R26R+ mouse demonstrating the AAo. Most but not all SMCs populating the AAo stain blue. Original magnification, ×200. (D) Transverse section of P2 Wnt1-Cre+/R26R+ mouse demonstrating robust Wnt1-Cre–mediated recombination in the DA. Original magnification, ×100. (E and F) Frontal sections of an E11.5 Wnt1-Cre+/R26R+ embryo demonstrating β-galactosidase activity restricted to the endocardial cushions in the right ventricle (RV) (F) and the AAo and DA (E). Original magnification, ×100. (G–J) Immunohistochemical analyses performed with anti-myocardin antibody demonstrating markedly diminished myocardin expression (brown nuclear stain) in the SMCs populating the internal carotid artery (ICA) (G and H) and aorta (Ao) (I and J) of P2 MyocdF/F/Wnt1-Cre+ mutant mice (H and J) compared with a control MyocdF/F littermate (G and I). Original magnification, ×300 (carotid); ×400 (aorta).

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