A New Editor of Smooth Muscle Phenotype
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Vascular smooth muscle cells (SMCs) comprise the muscular layer of blood vessel walls and mediate arterial tone and blood pressure. These cells possess a remarkable plasticity that allows mature contractile myocytes to dedifferentiate, enabling vessel growth and repair. This unusual ability to dedifferentiate is especially important because SMC phenotypic modulation contributes to multiple cardiovascular pathologies, including atherosclerosis and restenosis postangioplasty. In response to growth factors released at sites of injury, such as platelet-derived growth factor (PDGF), mature SMC can re-enter the cell cycle, become migratory, and dedifferentiate to a synthetic phenotype capable of extensive extracellular matrix deposition for vascular repair.1 Much of the research on SMC phenotypic switching has focused on transcriptional regulation of the contractile (differentiated) versus synthetic (dedifferentiated) phenotype. The new study by Fei and Cui et al2 in this issue makes the exciting discovery that RNA editing, leading to changes in mRNA splicing, is an important mechanism underlying SMC phenotypic switching.
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Differentiated SMC express a repertoire of SM-specific contractile proteins that give the cells their characteristic myocyte morphology and contractile properties. These include SM α-actin (ACTA2) and SM-myosin heavy chain (MYH11). These proteins are downregulated during SMC dedifferentiation, which makes them a tangible biochemical readout of cellular differentiation status.1 A substantial body of work has demonstrated that contractile protein induction occurs largely at the level of transcriptional control, mediated by core factors including the CArG element-binding protein serum response factor and cofactor myocardin.3 However, early studies of cultured SMC suggested that post-transcriptional mechanisms may underlie the PDGF-induced downregulation of contractile proteins. Notably, Acta2 mRNA levels decreased after PDGF treatment at an even greater rate than with the transcriptional inhibitor actinomycin D, and nuclear run-on indicated that nascent …