FMO2 Promotes Angiogenesis via Regulation of N‐Acetylornithine

Abstract Endothelial cell (EC) metabolism is an emerging target for proangiogenic treatment of ischemic diseases; however, little is known about the metabolic alterations in ECs during ischemic diseases or vessel development stages. By conducting single‐cell transcriptome analysis, this work identifies flavin‐containing monooxygenase 2 (FMO2) as a pivotal regulator under multiple ischemic conditions. Targeted EC compensation of FMO2 in the genetic ablation model proved its proangiogenic function in various ischemic models and in the developing retina. Metabolomics combined with EC single‐cell sequencing revealed N‐acetylornithine as the top‐ranked altered metabolite regulated by FMO2, which inactivates NOTCH1 expression through the transcriptome regulation of activating transcription factor 3 (ATF3). N‐acetylornithine delivery displays a proangiogenic therapeutic effect in the ischemic models. The therapeutic effects of FMO2 and N‐acetylornithine can also be recapitulated in human ECs. These findings provide insights into the proangiogenic mechanisms underlying FMO2 and N‐acetylornithine, revealing potential targets to treat ischemic disease.