Defective vascularization of HIF-1α-null embryos is not associated with VEGF deficiency but with mesenchymal cell death
Defective vascularization of HIF-1α-null embryos is not associated with VEGF deficiency but with mesenchymal cell death
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DOI：
10.1006/dbio.1999.9253
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发表时间：
1999-05-15
影响因子：
2.7
通讯作者：
Semenza, GL
中科院分区：
文献类型：
--
作者：
Kotch, LE;Iyer, NV;Semenza, GL
缺氧诱导因子 1 (HIF-1) 是一种由 HIF-1 α 和 HIF-1 β 亚基组成的二聚体转录因子，在哺乳动物 O-2 稳态中发挥重要作用。在 Hif1a(-/-) 基因敲除小鼠中，HIF-1 α 的完全缺乏导致心脏和血管畸形以及 E10.5 时的胚胎致死。在 E8.75 和 E9.25 之间，头部区域发生显着的血管退化和异常重塑，同时伴有明显的间充质细胞死亡。在 HIF-1 α 和 VEGF 缺陷胚胎中观察到类似的血管缺陷，并且 Hif1a(-/-) 胚胎干细胞中缺氧不会诱导 VEGF mRNA 表达。令人惊讶的是，与野生型胚胎相比，Hif1a(-/-) 胚胎表现出 VEGF mRNA 表达增加。在组织培养细胞中，VEGF mRNA 表达是由独立于 HIF-1 α 的葡萄糖剥夺诱导的，这提供了 Hif1a(-/-) 胚胎中 VEGF mRNA 表达增加的机制，其中缺乏足够的组织灌注导致 O-2 和葡萄糖剥夺。 Hif1a(-/-)胚胎中的血管缺陷与细胞死亡没有空间相关性，而不是与VEGF缺乏相关，细胞死亡的发生先于血管退化。 (C) 1999 年学术出版社。
Hypoxia-inducible factor 1 (HIF-1) is a dimeric transcription factor composed of HIF-1 alpha and HIF-1 beta subunits that plays an essential role in mammalian O-2 homeostasis. In Hif1a(-/-) knockout mice, complete deficiency of HIF-1 alpha resulted in cardiac and vascular malformations and embryonic lethality at E10.5. Between E8.75 and E9.25 striking vascular regression and abnormal remodeling occurred in the cephalic region concomitant with marked mesenchymal cell death. Similar vascular defects were observed in HIF-1 alpha- and VEGF-deficient embryos and VEGF mRNA expression was not induced by hypoxia in Hif1a(-/-) embryonic stem cells. Surprisingly, Hif1a(-/-) embryos demonstrated increased VEGF mRNA expression compared to wild-type embryos. In tissue culture cells, VEGF mRNA expression was induced by glucose deprivation independent of HIF-1 alpha, providing a mechanism for increased VEGF mRNA expression in Hif1a(-/-) embryos, in which absence of adequate tissue perfusion resulted in both O-2 and glucose deprivation. Rather than being associated with VEGF deficiency, the vascular defects in Hif1a(-/-) embryos were spatially correlated with cell death, the onset of which preceded vascular regression. (C) 1999 Academic Press.