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Oxygen\u2010dependent angiogenic responses are regulated by hypoxia\u2010inducible factor (HIF), the activity of which is controlled by prolyl 4\u2010hydroxylase domain (PHD) dioxygenases and the von Hippel\u2010Lindau (VHL) tumour suppressor. However, the role of NG2 cells in HIF\u2010regulated cerebral vascular homeostasis is incompletely understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To examine the HIF\/PHD\/VHL axis in neurovascular homeostasis, we used a Cre\u2010loxP\u2010based genetic approach in mice and targeted <jats:italic>Vhl<\/jats:italic>, <jats:italic>Epo<\/jats:italic>, <jats:italic>Phd1<\/jats:italic>, <jats:italic>Phd2<\/jats:italic>, <jats:italic>Phd3<\/jats:italic> and <jats:italic>Hif2a<\/jats:italic> in NG2 cells. Cerebral vasculature was assessed by immunofluorescence, RNA in situ hybridization, gene and protein expression analysis, gel zymography and in situ zymography.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Vhl<\/jats:italic> inactivation led to a significant increase in angiogenic gene and <jats:italic>Epo<\/jats:italic> expression. This was associated with EPO\u2010independent expansion of capillary networks in cortex, striatum and hypothalamus, as well as pericyte proliferation. A comparable phenotype resulted from the combined inactivation of <jats:italic>Phd2<\/jats:italic> and <jats:italic>Phd3<\/jats:italic>, but not from <jats:italic>Phd2<\/jats:italic> inactivation alone. Concomitant PHD1 function loss led to further expansion of the neurovasculature. Genetic inactivation of <jats:italic>Hif2a<\/jats:italic> in <jats:italic>Phd1\/Phd2\/Phd3<\/jats:italic> triple mutant mice resulted in normal cerebral vasculature.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our studies establish (a) that HIF2 activation in NG2 cells promotes neurovascular expansion and remodelling independently of EPO, (b) that HIF2 activity in NG2 cells is co\u2010controlled by PHD2 and PHD3 and (c) that PHD1 modulates HIF2 transcriptional responses when PHD2 and PHD3 are inactive.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13547","type":"journal-article","created":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T05:25:44Z","timestamp":1598505944000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Inactivation of HIF\u2010prolyl 4\u2010hydroxylases 1, 2 and 3 in NG2\u2010expressing cells induces HIF2\u2010mediated neurovascular expansion independent of 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