Molecular control of vascular smooth muscle cell differentiation and phenotypic plasticity

Although the primary role of vascular smooth muscle cells (SMCs) is contraction, they exhibit extensive phenotypic diversity and plasticity during normal development, during repair of vascular injury, and in disease states including arteriosclerosis and tumour angiogenesis. Results of recent studies indicate that there are unique as well as common transcriptional regulatory mechanisms that control expression of various SMC marker genes within vascular SMC subtypes, and that these mechanisms are complex and dynamic even at the single cell level. This chapter will review recent progress in our understanding of the complex processes, environmental cues, and genes that control development of vascular SMCs from embryonic stem cells, as well as mechanisms that contribute to phenotypic switching of SMCs following vascular injury or in disease states. A major focus will be to summarize recent studies in our laboratory and others showing the importance of CArG-SRF-myocardin-dependent mechanisms and epigenetic controls in regulation of vascular SMC lineage. Of major interest, we have shown that SMC precursor cells acquire a unique pattern of epigenetic changes (i.e. chromatype) during early development that distinguish them from other cell lineages, and makes them permissive for activation of cell selective genes required for their specialized function. In addition, we show that phenotypic switching of SMCs in response to PDGF BB in vitro, or vascular injury in vivo is associated with loss of a subset of activating histone modifications at gene loci encoding SMC marker genes, but retention of additional markers such as H3K4 methylation. We postulate that the latter epigenetic changes may provide a mechanism for 'cell lineage memory' during reversible phenotypic switching of vascular SMCs.