ACSS2 modulates endothelial glycolysis in angiogenesis

Although the molecular pathways regulating endothelial glycolysis are well characterized, the metabolic mechanisms underlying hypoxia-induced glycolytic activation during angiogenesis remain poorly understood. Here, we show that acetyl-CoA synthetase 2 (ACSS2) serves as a critical metabolic modulator, coupling acetate utilization with glycolytic flux to control EC function and angiogenesis.

The high level of ACSS2-mediated acetate-to-acetyl-CoA conversion in angiogenic front ECs sustains acetyl-CoA levels, which are essential for EC proliferation and retinal vascularization. Conversely, endothelial-specific Acss2 deletion disrupts pathological angiogenesis and normalizes tumor vasculature. Mechanistically, ACSS2 maintains hypoxia-inducible factor 1α transcriptional activity and stabilizes glucose transporter 1, thereby preserving glycolysis.