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By conducting single\u2010cell transcriptome analysis, this work identifies flavin\u2010containing 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\u2010cell sequencing revealed N\u2010acetylornithine as the top\u2010ranked altered metabolite regulated by FMO2, which inactivates NOTCH1 expression through the transcriptome regulation of activating transcription factor 3 (ATF3). N\u2010acetylornithine delivery displays a proangiogenic therapeutic effect in the ischemic models. The therapeutic effects of FMO2 and N\u2010acetylornithine can also be recapitulated in human ECs. 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