MYOCARDIN AND VASCULAR SMOOTH MUSCLE

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The differential patterning of smooth muscle cells (SMCs) and pericytes within specific blood vessels ultimately defines and distinguishes the functional properties of the arteries, veins and capillaries. SMC phenotype and patterning, in turn, are determined via transcriptional programs that respond to developmental and environmental signals and cues. We have used transgenic and gene targeting strategies to elucidate the transcriptional programs that regulate vascular SMC differentiation. Our group and others have reported recently that the SAP domain transcription factor, myocardin, plays a critical role in SMC differentiation. Preliminary studies presented herein demonstrate that: i) myocardin is expressed in a precise developmentally regulated pattern in vascular and visceral SMCs, ii) forced expression of myocardin in non-SMCs activates multiple SMC-specific transcriptional regulatory elements, iii) forced expression of myocardin activates SMC-restricted genes in undifferentiated embryonic stem (ES) cells, and iv) expression of adominant-negative myocardin mutant protein or myocardin siRNA in SMCs represses activity of the SMC-specific SM22alpha-promoter. Together these studies suggest the central hypothesis that will be examined in the proposed studies: myocardin plays a critical role in the SRF-dependent transcriptional program that regulates SMC differentiation and phenotype. The overall goat of this project is to elucidate the molecular basis of myocardin-induced SMC differentiation. The specific aims are to: 1) Examine the cell autonomous functions of myocardin in SMCs during embryonic development, and on maintenance of the SMC phenotype, 2) Examine the molecular mechanisms underlying the activity and specificity of the myocardin-SRF dependent transcriptional program that regulates SMC differentiation, and 3) Generate and characterize mice containing null and conditioned mutations in the myocardin gene. At a basic level these studies will provide new insights into the transcriptional programs regulating SMC differentiation and modulation of SMC phenotype. As such, these studies are relevant to understanding the pathogenesis of atherosclerosis and other vascular proliferative syndromes.