ERG preserves endothelial identity to limit atherosclerosis

Endothelial function is a critical safeguard against atherosclerosis. At atheroprone sites, the normally protective arterial endothelium can undergo endothelial-to-mesenchymal transition (EndMT), but the timing, contribution, and reversibility of this process during atherogenesis are poorly understood. Here we explored the impact of endothelial identity loss in atheroprogression through modulation of the ETS transcription factor ERG, a principal endothelial identity regulator. Inducible endothelial Erg deletion markedly increased plaque in hypercholesterolemic mice. Endothelial-lineage tracing and single-cell transcriptomics revealed that ERG loss induced profound dedifferentiation, followed by mesenchymal fate acquisition and migration and expansion of EndMT cells into the plaque, which interacted with pro-atherosclerotic macrophages and smooth muscle cells. Endothelial identity loss also promoted early disruption of junctional signaling and barrier, leading to enhanced lipid uptake, and foam cell accumulation in typically atheroresistant regions. Investigation of ERG in human atherosclerosis identified reduced chromatin accessibility and expression in plaques, where endothelial cell transcriptional changes paralleled murine Erg deletion. Restoration of ERG in cultured EndMT cells reversed mesenchymal and restored endothelial cell gene regulatory programs. These findings implicate ERG downregulation as a novel driver of endothelial dysfunction in atherosclerosis, reinforce the link between EndMT and atheroprogression, and highlight ERG as a mechanism to restore endothelial identity.