Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells

Abstract

Smooth muscle cells (SMCs) play a key role in atherogenesis. However, mechanisms regulating expansion and fate of pre-existing SMCs in atherosclerotic plaques remain poorly defined. Here we show that multiple SMC progenitors mix to form the aorta during development. In contrast, during atherogenesis, a single SMC gives rise to the smooth muscle-derived cells that initially coat the cap of atherosclerotic plaques. Subsequently, highly proliferative cap cells invade the plaque core, comprising the majority of plaque cells. Reduction of integrin β3 (Itgb3) levels in SMCs induces toll-like receptor 4 expression and thereby enhances Cd36 levels and cholesterol-induced transdifferentiation to a macrophage-like phenotype. Global Itgb3 deletion or transplantation of Itgb3(−/−) bone marrow results in recruitment of multiple pre-existing SMCs into plaques. Conditioned medium from Itgb3-silenced macrophages enhances SMC proliferation and migration. Together, our results suggest SMC contribution to atherogenesis is regulated by integrin β3-mediated pathways in both SMCs and bone marrow-derived cells.

Imaging mass spectrometry reveals heterogeneity of proliferation and metabolism in atherosclerosis

“…Atherosclerotic lesions grow via recruitment of bone marrow-derived monocytes and local proliferation of lesional macrophages and VSMCs (14)(15)(16). This study using MIMS identified higher rates of proliferation in foam cells as compared with prior reports (15,17).…”

“…In contrast to foam cells, medial VSMC proliferation occurred in a more discrete subpopulation of cells. Whether these 15 N-positive VSMCs will preferentially contribute to plaque growth is the subject of ongoing work coupling lineage-tracing approaches with MIMS (14,19). However, we did detect lipid-laden VSMCs directly underlying the intima (Figure 3), indicative of foam cell-like changes.…”

Induced osteogenic differentiation of human smooth muscle cells as a model of vascular calcification

“…Variance concerning the expression of CD140b could only be observed when measured as surface protein, not in the gene expression analysis. This discrepancy might emerge from regulated trafficking of CD140b 47 that seems to be of relevance during SMC recruitment to the fibrous cap 14,48 and further illustrates SMC plasticity.…”

Differential expression and bioinformatics analysis of circRNA in PDGF-BB-induced vascular smooth muscle cells

“…Moreover, VSMCs migrate and proliferate to the surrounding of the necrotic core and play an important role in creating a fibrous cap that stabilizes the atherosclerotic plaque [3,4].Moreover, VSMCs can differentiate into many other cell types found in the plaque core, suggesting that these cells might participate in multiple processes underlying atherosclerotic plaque stability [5][6][7][8].…”