**11. Macrophage influence over SMC activation**

Macrophages and SMCs play pivotal roles in vascular diseases. The evidence suggests the interplay between these cell lineages. Macrophages promote SMC activation. In vitro coculture studies showed macrophage-derived PDGF promotes SMC growth [128]. IL-6 released by macrophages promotes SMC MMP-1 production [129]. Several in vivo studies identified macrophage MCP-1 and its receptor CCR2 depletion as instigators of SMC activation [130-132]. Macrophage affects SMC differentiation through mechanisms of PDGF-BB, a major macro‐ phage product. PDGF-BB suppresses SMC differentiation markers as gauged by the expression of SM α-actin, SM-MHC, and α-tropomyosin [30]. In a rabbit model of atherosclerosis, lipid lowering decreases the accumulation of macrophages expressing PDGF-B, and concomitantly increases the differentiated state of intimal SMCs, as gauged by increased expression of the SM-MHC isoform SM2 [26]. While these intimal SMCs regained SM2 expression, they decreased MMP expression. As discussed, more recent evidence indicates that BM-derived cells in the circulating blood (e.g., a subset of activated monocytes, SMPC) may differentiate into smooth muscle–like cells and contribute to the development of vascular lesions and the onset of their clinical complications [14].
