title: Myocardin is required for maintenance of vascular and visceral smooth muscle homeostasis during postnatal development.
abstract: Myocardin is a muscle-restricted transcriptional coactivator that activates a serum response factor (SRF)-dependent gene program required for cardiogenesis and embryonic survival. To identify myocardin-dependent functions in smooth muscle cells (SMCs) during postnatal development, mice harboring a SMC-restricted conditional, inducible Myocd null mutation were generated and characterized. Tamoxifen-treated SMMHC-Cre(ERT2)/Myocd(F/F) conditional mutant mice die within 6 mo of Myocd gene deletion, exhibiting profound derangements in the structure of great arteries as well as the gastrointestinal and genitourinary tracts. Conditional mutant mice develop arterial aneurysms, dissection, and rupture, recapitulating pathology observed in heritable forms of thoracic aortic aneurysm and dissection (TAAD). SMCs populating arteries of Myocd conditional mutant mice modulate their phenotype by down-regulation of SMC contractile genes and up-regulation of extracellular matrix proteins. Surprisingly, this is accompanied by SMC autonomous activation of endoplasmic reticulum (ER) stress and autophagy, which over time progress to programmed cell death. Consistent with these observations, Myocd conditional mutant mice develop remarkable dilation of the stomach, small intestine, bladder, and ureters attributable to the loss of visceral SMCs disrupting the muscularis mucosa. Taken together, these data demonstrate that during postnatal development, myocardin plays a unique, and important, role required for maintenance and homeostasis of the vasculature, gastrointestinal, and genitourinary tracts. The loss of myocardin in SMCs triggers ER stress and autophagy, which transitions to apoptosis, revealing evolutionary conservation of myocardin function in SMCs and cardiomyocytes.
authors: Cardiovascular Institute and Departments of.
authors: Jianhe
authors: J
authors: Huang
authors: Cardiovascular Institute and Departments of.
authors: Tao
authors: T
authors: Wang
authors: Radiology and.
authors: Alexander C
authors: AC
authors: Wright
authors: Cardiovascular Institute and Departments of.
authors: Jifu
authors: J
authors: Yang
authors: Cardiovascular Institute and Departments of.
authors: Su
authors: S
authors: Zhou
authors: Cardiovascular Institute and Departments of.
authors: Li
authors: L
authors: Li
authors: Cardiovascular Institute and Departments of.
authors: Jisheng
authors: J
authors: Yang
authors: Cardiovascular Institute and Departments of.
authors: Aeron
authors: A
authors: Small
authors: Cardiovascular Institute and Departments of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 michael.parmacek@uphs.upenn.edu.
authors: Michael S
authors: MS
authors: Parmacek
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001014:Aortic Aneurysm / Q000378:metabolism*; D017209:Apoptosis; D001343:Autophagy; D041981:Gastrointestinal Tract / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006706:Homeostasis; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology*; D010641:Phenotype; D013629:Tamoxifen / Q000737:chemistry; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*; D014566:Urogenital System / Q000378:metabolism; D000099251:Myocardin
chemical_list: D009687:Nuclear Proteins; D013629:Tamoxifen; D015534:Trans-Activators; D000099251:Myocardin
keywords: ER stress; apoptosis; autophagy; smooth muscle cell; transcriptional coactivator