MYOCARDIN AND VASCULAR SMOOTH MUSCLE

平滑肌细胞（SMCs）和周细胞在特定血管中的差异模式最终定义并区分了动脉、静脉和毛细血管的功能特性。SMC的表型和模式是通过转录程序决定的，转录程序对发育和环境信号和线索作出反应。我们已经使用转基因和基因靶向策略来阐明调控血管SMC分化的转录程序。我们的团队和其他人最近报道了SAP结构域转录因子，心肌素，在SMC分化中起关键作用。本文提出的初步研究表明：i)心肌素在血管和内脏SMCs中以一种精确的发育调节模式表达，ii)心肌素的强迫表达

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.