differential but complementary hif1 and hif2 transcriptional regulation effective vascular regeneration could provide therapeutic benefit for multiple pathologies especially in chronic peripheral artery disease pad and myocardial ischemia the hypoxia inducible factors hifs mediate the cellular transcriptional response to hypoxia and regulate multiple processes that are required for angiogenesis to ultimately restore perfusion and oxygen supply in endothelial cells both hif1 and hif2 are known to contribute to this role however the extent and individual roles of each of these hif remain unclear to characterize the individual roles of hif we sequenced the transcriptional outputs of stabilized forms of hif1 and hif2 where they regulated 701 and 1454 genes respectively hif1 transcription primarily regulated metabolic reprogramming whereas hif2 exerted a larger role in regulating angiogenic extracellular signaling guidance cues and extracellular matrix remodeling factors furthermore hif2 almost exclusively regulated a large and diverse subset of transcription factors and coregulators that contribute to its diverse roles in hypoxia further understanding of how hifs regulate cellular processes in hypoxia and angiogenesis could offer new avenues to modulate physiological angiogenesis to enhance revascularisation in ischemic conditions and other pathologies