Polycomb Repressive Complex 2 drives flow-sensitive endothelial states underlying vascular inflammation and disease

Atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide, is driven by endothelial cell (EC) inflammatory activation and counterbalanced by protective mechanosensitive transcription factors Klf2 and Klf4 (Klf2/4). Plaques initiate in arterial curves or branches where disturbed shear stress (DSS) restrains Klf2/4 expression and promotes inflammatory activation of the endothelium. Importantly, DSS determines plaque vulnerability to rupture, the event that precipitates heart attack or stroke in advanced disease. However, the central determinants of endothelial inflammatory mechanotransduction and their interventional targeting to treat ASCVD pathology remain underexplored. Here, we identify Polycomb Repressive Complex (PRC) 2 as a potent, therapeutically targetable driver of vascular endothelial inflammation and ASCVD progression. PRC2 trimethylates Histone H3 Lysine27 in gene promoters/enhancers, including Klf2/4, to block gene transcription. Integrated mechanistic computation and experimental studies identified PRC2 as a central determinant of the EC state transition to inflammatory activation. PRC2 activity is elevated in endothelium from human ASCVD lesions. In murine models of acute and chronic vascular inflammation, interventional treatment with tazemetostat, a Federal Drug Administration (FDA)-approved inhibitor of the PRC2 methyltransferase EZH2, reduced endothelial inflammatory genes, slowed disease progression, and drastically improved markers of plaque stability. This study elucidates a fundamental epigenetic mechanism in vascular inflammation and suggests a potential treatment for advanced and chronic cardiovascular inflammatory diseases.