Abstract

Hypoxia adaptation can partially improve and restore the composition, structure, and function of blood vessels, thereby enhancing the prognosis of related diseases such as stroke. However, the underlying molecular mechanisms of hypoxia adaptation remain elusive. In this study, multi-omics analysis was performed across yeast, zebrafish, and mouse, revealing that sphingolipid metabolism is crucial for hypoxic adaptation. We found that the expression of the key protein ceramide synthase 2 (CerS2) in mammals and its yeast ortholog very-long-chain ceramide synthase LAC1 was up-regulated. CerS2 and LAC1 are key enzymes that promote hypoxic angiogenesis by increasing the synthesis of C24:1, and this function is highly conserved across species and throughout evolution. CerS2 and LAC1 biosynthesize the long-chain unsaturated ceramide C24:1, which, via its double-bond structure, specifically binds to ROCK2 to activate HIF-1α, thereby up-regulating the expression of vascular endothelial growth factor (VEGF) and increasing AKT phosphorylation. Consequently, this process significantly enhances angiogenesis and improves blood flow perfusion in a mouse model of ischemic stroke. This study deepens our understanding of the function of unsaturated ceramides and reveals the unique mechanism of C24:1 in angiogenesis and protection under hypoxic conditions.