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Differential But Complementary Hif1 Alpha And Hif2 Alpha Transcriptional Regulation

MOLECULAR THERAPY(2018)

Cited 87|Views10
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Abstract
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 alpha and HIF2 alpha are known to contribute to this role; however, the extent and individual roles of each of these HIF alpha remain unclear. To characterize the individual roles of HIF alpha, we sequenced the transcriptional outputs of stabilized forms of HIF1 alpha and HIF2 alpha, where they regulated 701 and 1,454 genes, respectively. HIF1 alpha transcription primarily regulated metabolic reprogramming, whereas HIF2 alpha exerted a larger role in regulating angiogenic extracellular signaling, guidance cues, and extracellular matrix remodeling factors. Furthermore, HIF2 alpha 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 revascular-isation in ischemic conditions and other pathologies.
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Key words
HIF1a,HIF2a,EPAS1,transcription factor,transcription,hypoxia,cardiovascular disease,RNA-seq,angiogenesis
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