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 HIF1á and HIF2á are known to contribute to this role; however, the extent and individual roles of each of these HIFá remain unclear. To characterize the individual roles of HIFá, we sequenced the transcriptional outputs of stabilized forms of HIF1á and HIF2á, where they regulated 701 and 1,454 genes, respectively. HIF1á transcription primarily regulated metabolic reprogramming, whereas HIF2á exerted a larger role in regulating angiogenic extracellular signaling, guidance cues, and extracellular matrix remodeling factors. Furthermore, HIF2á 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.
Basic Helix-Loop-Helix Transcription Factors Cell Line