Complex regulation and function of the inflammatory smooth muscle cell phenotype in atherosclerosis

Abstract

Vascular smooth muscle cell (SMC) phenotypic modulation plays a key role in atherosclerosis and is classically defined as a switch from a 'contractile' phenotype to a 'synthetic' phenotype, whereby genes that define the contractile SMC phenotype are suppressed and proliferation and/or migratory mechanisms are induced. There is also evidence that SMCs may take on a 'proinflammatory' phenotype, whereby SMCs secrete cytokines and express cell adhesion molecules, e.g. IL-8, IL-6, and VCAM-1, respectively, which may functionally regulate monocyte and macrophage adhesion and other processes during atherosclerosis. Factors that drive the inflammatory phenotype are not limited to cytokines but also include hemodynamic forces imposed on the blood vessel wall and intimate interaction of endothelial cells with SMCs, as well as changes in matrix composition in the vessel wall. However, it is critical to recognize that our understanding of the complex interaction of these multiple signal inputs has only recently begun to shed light on mechanisms that regulate the inflammatory SMC phenotype, primarily through models that attempt to recreate this environment ex vivo. The goal of this review is to summarize our current knowledge in this area and identify some of the key unresolved challenges and questions requiring further study.

Fig. 1

SMCs can be in proximity to macrophages (MΦ) and express VCAM-1 in vascular disease. a SMCs within the neointima are in close proximity and can physically interact with other cell types, including endothelial cells, monocytes, and macrophages (yellow dashed line is the MΦ/SMC interface; adapted from Stary et al. [3]). These interactions can influence SMC phenotype, promoting inflammatory responses. b SMCs present in the intimal and medial layers of human coronary arteries can express the adhesion molecule VCAM-1 (blue – VCAM-1, red – α-smooth muscle actin, green – elastin; Hastings et al. [5]). c In the ApoE–/– mouse, VCAM-1 expression is prevalent in the intimal regions of the inner curvature of the aortic arch, prior to lesion formation (red – VCAM-1, blue – nuclei, green – elastin [unpubl. observation]). EC = Endothelial cell; I = intima; M = media; L= lumen.

Fig. 2

Complex regulation and function of the inflammatory SMC phenotype in atherosclerosis. 2.1 Disturbed low, time-averaged shear stresses cause priming of endothelial cells (EC) towards a proinflammatory state, inducing proteins including IL-8, MCP-1, VCAM-1, and ICAM-1. All of these proteins are involved in capture and firm adhesion of monocytes to the endothelium. 2.2 oxLDL binds to LOX-1, which can increase cytokine production (TNFα, MCP-1, and IL-8) and adhesion molecule expression in NF-κB-dependent pathways. 2.3 The matrix that SMCs bind to can induce modulation towards a proinflammatory phenotype. Cytokines stimulate FN production which can activate NF-κB and/or NFAT through integrin signaling, though the direct mechanism inducing SMC inflammation is not well established. 2.4 It remains unclear whether macrophage interaction with ECs and SMCs is having pro/anti-inflammatory effects on each cell phenotype. 2.5 Disturbed shear stresses are known to cause IL-8 secretion, which was recently demonstrated to inhibit expression of VCAM-1 in SMCs, thus demonstrating one mechanism by which a mechanical stimulus influences EC/SMC cross-talk, and ultimately the SMC inflammatory state. Green ECs and red SMCs indicate transition to the activated, inflammatory state.