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ACSS2 modulates endothelial glycolysis in angiogenesis

ABSTRACT: Endothelial cells (ECs) sustain high glycolytic flux and display remarkable metabolic plasticity. 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. Pyruvate dehydrogenase kinase 4 knockdown rescues metabolic and functional defects in ACSS2-deficient ECs, revealing acetyl-CoA homeostasis as a lynchpin of hypoxic endothelial metabolism. Collectively, our work establishes ACSS2 as a pivotal regulator of vascular development and proposes targeting acetate metabolism as a strategy to modulate pathological angiogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301613 | GEO | 2026/06/01

REPOSITORIES: GEO

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