Inactivation of HIF-prolyl 4-hydroxylases 1, 2 and 3 in NG2-expressing cells induces HIF2-mediated neurovascular expansion independent of erythropoietin.
Inactivation of HIF-prolyl 4-hydroxylases 1, 2 and 3 in NG2-expressing cells induces HIF2-mediated neurovascular expansion independent of erythropoietin.
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DOI：
10.1111/apha.13547
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Haase VH
中科院分区：
文献类型：
--
作者：
Urrutia AA;Guan N;Mesa-Ciller C;Afzal A;Davidoff O;Haase VH
脑内NG2细胞由周细胞和NG2胶质细胞组成，在脑缺氧反应的执行中发挥重要作用，包括诱导周细胞的促红细胞生成素（EPO）。氧依赖性血管生成反应是由缺氧诱导因子（HIF）调控的，HIF的活性由脯氨酸4‐羟化酶结构域（PHD）双加氧酶和von Hippel‐Lindau （VHL）肿瘤抑制因子控制。然而，NG2细胞在HIF调控的脑血管稳态中的作用尚不完全清楚。为了研究HIF/PHD/VHL轴在神经血管稳态中的作用，我们在小鼠中使用了基于Cre - loxP的遗传方法，并在NG2细胞中靶向VHL、Epo、Phd1、Phd2、Phd3和Hif2a。采用免疫荧光法、RNA原位杂交法、基因和蛋白表达法、凝胶酶谱法和原位酶谱法评价大鼠的脑血管功能。Vhl失活导致血管生成基因和Epo表达显著增加。这与皮层、纹状体和下丘脑中不依赖EPO的毛细血管网络扩张以及周细胞增殖有关。可比较的表型是由Phd2和Phd3联合失活引起的，而不是由Phd2单独失活引起的。伴随的PHD1功能丧失导致神经血管进一步扩张。在Phd1/Phd2/Phd3三重突变小鼠中，Hif2a基因失活导致脑血管系统正常。我们的研究证实了(a) NG2细胞中HIF2的激活独立于EPO促进神经血管扩张和重塑，(b) NG2细胞中HIF2的活性由PHD2和PHD3共同控制，(c) PHD1在PHD2和PHD3失活时调节HIF2的转录反应。
NG2 cells in the brain are comprised of pericytes and NG2 glia and play an important role in the execution of cerebral hypoxia responses, including the induction of erythropoietin (EPO) in pericytes. Oxygen‐dependent angiogenic responses are regulated by hypoxia‐inducible factor (HIF), the activity of which is controlled by prolyl 4‐hydroxylase domain (PHD) dioxygenases and the von Hippel‐Lindau (VHL) tumour suppressor. However, the role of NG2 cells in HIF‐regulated cerebral vascular homeostasis is incompletely understood. To examine the HIF/PHD/VHL axis in neurovascular homeostasis, we used a Cre‐loxP‐based genetic approach in mice and targeted Vhl, Epo, Phd1, Phd2, Phd3 and Hif2a in NG2 cells. Cerebral vasculature was assessed by immunofluorescence, RNA in situ hybridization, gene and protein expression analysis, gel zymography and in situ zymography. Vhl inactivation led to a significant increase in angiogenic gene and Epo expression. This was associated with EPO‐independent expansion of capillary networks in cortex, striatum and hypothalamus, as well as pericyte proliferation. A comparable phenotype resulted from the combined inactivation of Phd2 and Phd3, but not from Phd2 inactivation alone. Concomitant PHD1 function loss led to further expansion of the neurovasculature. Genetic inactivation of Hif2a in Phd1/Phd2/Phd3 triple mutant mice resulted in normal cerebral vasculature. 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‐controlled by PHD2 and PHD3 and (c) that PHD1 modulates HIF2 transcriptional responses when PHD2 and PHD3 are inactive.
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