HIF‐1α is required for solid tumor formation and embryonic vascularization

The transcriptional response to lowered oxygen levels is mediated by the hypoxia‐inducible transcription factor (HIF‐1), a heterodimer consisting of the constitutively expressed aryl hydrocarbon receptor nuclear translocator (ARNT) and the hypoxic response factor HIF‐1α. To study the role of the transcriptional hypoxic response in vivo we have targeted the murine HIF‐1α gene. Loss of HIF‐1α in embryonic stem (ES) cells dramatically retards solid tumor growth; this is correlated with a reduced capacity to release the angiogenic factor vascular endothelial growth factor (VEGF) during hypoxia. HIF‐1α null mutant embryos exhibit clear morphological differences by embryonic day (E) 8.0, and by E8.5 there is a complete lack of cephalic vascularization, a reduction in the number of somites, abnormal neural fold formation and a greatly increased degree of hypoxia (measured by the nitroimidazole EF5). These data demonstrate the essential role of HIF‐1α in controlling both embryonic and tumorigenic responses to variations in microenvironmental oxygenation.

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