Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA.
Department of Genetics, Yale University School of Medicine, New Haven, CT, 06511, USA.
Nat Commun. 2018 May 25;9(1):2073. doi: 10.1038/s41467-018-04447-7.
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.
平滑肌细胞（SMCs）在动脉粥样硬化的发生中起着关键作用。然而，调节动脉粥样硬化斑块中预先存在的 SMC 增殖和命运的机制仍未得到明确界定。在这里，我们表明，多个 SMC 祖细胞在发育过程中混合形成主动脉。相比之下，在动脉粥样硬化发生过程中，单个 SMC 产生最初覆盖动脉粥样硬化斑块帽的平滑肌衍生细胞。随后，高增殖的帽细胞侵入斑块核心，构成斑块细胞的大多数。SMC 中整合素 β3（Itgb3）水平的降低诱导 Toll 样受体 4 的表达，从而增强 Cd36 水平并诱导胆固醇诱导的向巨噬细胞样表型的转化。Itgb3 基因敲除或 Itgb3 骨髓移植会导致多个预先存在的 SMC 招募到斑块中。沉默巨噬细胞的条件培养基可增强 SMC 的增殖和迁移。总之，我们的研究结果表明，整合素 β3 介导的 SMC 和骨髓来源细胞中的途径调节 SMC 对动脉粥样硬化形成的贡献。
