Defective vascularization of HIF-1α-null embryos is not associated with VEGF deficiency but with mesenchymal cell death

Hypoxia-inducible factor 1 (HIF-1) is a dimeric transcription factor composed of HIF-1α and HIF-1β subunits that plays a essential role in mammalian O₂ homeostasis. In Hif1a(-/-) knocknout mice, complete deficiency of HIF-1α 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-1α- 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-1α, providing a mechanisms for increased VEGF mRNA expression in Hif1a(-/-) embryos, in which absence of adequate tissue perfusion resulted in both O₂ 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.