Atherosclerosis Cohorts Raw Images

Vascular smooth muscle cells (SMCs) undergo phenotype switching to acquire various fates in response to pathological stimuli. Among these, “synthetic” SMCs—defined by migration, proliferation, and extracellular matrix production—accumulate in atherosclerotic lesions and contribute to fibrous cap formation. The mechanisms driving this synthetic transition remain unclear. Here we identify <i>PRDM16</i>, a gene linked to cardiovascular disease, as a critical transcriptional repressor of the synthetic SMC phenotype. <i>PRDM16 </i>expression declined during SMC modulation, and its deletion in mice induced a synthetic program across all SMC subtypes even without pathological stimuli. Under atherogenic conditions, <i>PRDM16</i>-deficiency resulted in the formation of fibroproliferative plaques with more synthetic SMCs and fewer foam cells. Conversely, enforced PRDM16 expression suppressed SMC migration, proliferation, and fibrosis. Mechanistically, PRDM16 occupied chromatin and suppressed activating marks at synthetic loci. These findings establish PRDM16 as a gatekeeper of SMC fate and reveal its role in shaping atherosclerotic plaque composition.

血管平滑肌细胞（vascular smooth muscle cells，SMCs）会发生表型转换以获得多种细胞命运，响应病理刺激。其中，以迁移、增殖及细胞外基质合成为特征的“合成型”血管平滑肌细胞，会在动脉粥样硬化病变中聚集，并参与纤维帽的形成。目前，驱动该合成型转换的分子机制仍不明确。本研究鉴定出PRDM16——一种与心血管疾病相关的基因——作为合成型血管平滑肌细胞表型的关键转录抑制因子。在血管平滑肌细胞表型调控过程中，PRDM16的表达水平会下调；而在小鼠中敲除该基因，即使在无病理刺激的情况下，也能诱导所有血管平滑肌细胞亚型表达合成型基因程序。在致动脉粥样硬化条件下，PRDM16缺失会导致纤维增殖性斑块的形成，该斑块中合成型血管平滑肌细胞占比更高，泡沫细胞占比更低。反之，过表达PRDM16则会抑制血管平滑肌细胞的迁移、增殖及纤维化过程。从机制层面来看，PRDM16可结合染色质，并抑制合成型基因位点的激活型表观遗传标记。本研究结果证实PRDM16是血管平滑肌细胞命运的守门人，并揭示了其在塑造动脉粥样硬化斑块组成中的作用。