biostudies-literatureWang JFundamental Research Funds for the Central UniversitiesNational Key R&D Program of ChinaKey R&D projects of Zhejiang ProvinceCentral Guidance on Local Science and Technology Development Fund of Zhejiang ProvinceNational Natural Science Foundation of ChinaNational Key Research and Development Program of ChinaBinjiang Institute of Zhejiang UniversityTransvascular Implantation Devices Research Institutee06618https://www.ebi.ac.uk/biostudies/studies/S-EPMC12752610biostudies-literatureUnknown12(48)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 (ATF3Advanced science (Weinheim, Baden-Wurttemberg, Germany)FMO2 Promotes Angiogenesis via Regulation of N-Acetylornithine.PMC127526108243001382370240226-2023-001562024ZY01044ZY202205SMKY00282030014ZY202205SMKY0012021C030972024YFC30445002023YFA18007002023C03086KY0120250022023YFA180070482225004226‐2023‐001568220027582070253Ruan YChen JHu XFu ZLi QZhong ZWang JLi MChen YZhu WNi CXiao CZhao JNan JXu YWu XfalseFMO2 Promotes Angiogenesis via Regulation of N-Acetylornithine.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 (ATF32025-01-01T00:00:00Z2025 Dec2026-06-06T08:56:49.082Z2026-05-28T03:12:12.322ZS-EPMC127526104105353310.1002/advs.202506618