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. Mice harboring a null mutation in the myocardin gene (Myocd) exhibit a block in cardiomyocyte proliferation accompanied by a dramatic increase in cardiomyocyte apoptosis, leading to lethality at midgestation (5). Ablation of Myocd in the adult heart leads to heart failure and lethality attributable to a disruption in sarcomere structure accompanied by programmed cell death (6). By contrast, mice harboring a neural crest-restricted ablation of Myocd die in the perinatal period from patent ductus arteriosus (PDA) attributable to a block in the SMC contractile gene program (7).After more than a decade of study, fundamental questions regarding the function of myocardin in vascular SMCs during postnatal development as well as visceral SMCs populating the gastrointestinal and genitourinary tracts remain unanswered. Is myocardin required for SMC contractile gene expression and maintenance of arterial tone? What role, if any, does myocardin play in regulating expression of SRF-regulated SMC contractile genes in visceral SMCs? Do the related transcriptional coactivators MKL-1 and/or MKL-2 mediate redundant functions with myocardin in the adult vasculature or visceral tissues (4)? Is myocardin required for survival of vascular SMCs in a manner analogous to that it plays in c...

Magnesium ion leachables induce a conversion of contractile vascular smooth muscle cells to an inflammatory phenotype

“…Since the suppression of the contractile genes and the promotion of the inflammatory players were observed at the transcriptional level, we focused on transcriptional regulators such as myocardin (encoded by Myocad ) and KLF4 (encoded by Klf4 ). Myocardin is a well‐known coactivator of serum response factor and the key transactivator of contractile genes . The inflammatory activation of vSMCs accelerated when myocardin was deficient or reduced in vitro and in vivo .…”

Selective expression of TSPAN2 in vascular smooth muscle is independently regulated by TGF‐β1/SMAD and myocardin/serum response factor

“…Emerging evidence indicates that MYOCD and the TGF-b/SMAD pathway are indispensable to vascular development and homeostasis (36,(46)(47)(48)(49)(50)(51). The deficiency of key components of either pathway, such as MYOCD, SMAD4, or TGFbR in VSMCs, causes defects in VSMC differentiation, vascular development, and arterial diseases, such as aneurysms (51)(52)(53)(54). It will be important to elucidate whether these phenotypes are secondary to the perturbation in VSMC differentiation, or if they relate to other distinct roles of MYOCD and TGF-b signaling in inflammation and cell death.…”

Myocardin-related transcription factors are required for cardiac development and function

“…In contrast, cardiac-specific deletion of myocardin with an αMHC-Cre transgene, which becomes active slightly later in development, causes adult onset heart failure accompanied by sarcomere disruption, but no overt cardiac morphological defects (Huang et al, 2009), though a fraction of these animals succumb to early postnatal lethality. In addition to its role in postnatal cardiac function, myocardin is also essential for vascular homeostasis; deletion of myocardin in smooth muscle cells in adult animals led to lethality within 6 months, accompanied by defects in arterial structure and visceral smooth muscle maintenance (Huang et al, 2015). …”