Vascular Smooth Muscle Cells
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Decades of work have shown that vascular smooth muscle cell (SMC) phenotypes are controlled by cues received from the local environment.1–3 When nestled into a cage of cross-linked collagen and elastin of its own making,4 medial SMCs exhibit a fully differentiated phenotype conferred by the transcriptional activity of myocardin and serum response factor (SRF) and reinforced by the stabilizing roles of miR-143/145.2,3,5–7 The central MADS (MCM1, Agamous, Deficiens, SRF) box of SRF is an ancient DNA-binding regulatory platform8,9 that formed a partnership with the basic and polyglutamine domains of myocardin family proteins early in metazoan evolution.10–12 This evolutionary innovation allowed for the formation of an extremely versatile type of muscle cell now found in the walls of almost all lumen-containing organs and tissues in adults and as a transitional form in the embryonic heart.
Vascular SMCs Adopt Macrophage-Like Phenotypes
Recent studies, many of which have been published or discussed in the pages of ATVB, extend the range of phenotypes exhibited by vascular SMCs to those previously thought to be found only in cells of myeloid origin.13–17 These papers use modern genetic tools to build upon observations made during the past 30 years on SMC responses to injury and cholesterol loading.18–21 These early studies identified and characterized the SMC foam cell, but investigators lacked modern transgenic methods to assess the frequency of SMC foam cell formation in atherogenesis. The surprising result described in recent reports is not that SMC to macrophage-like cell transitions occur in atherosclerosis, but rather the evidently large extent to which a SMC origin can account for cells that express common macrophage markers in the plaque.14–17,22 The high frequency of SMC-derived plaque macrophages may begin …