Hypoxia‐induced angiogenesis in the conditional HIF‐1α deficient and HIF‐2α deficient mice (887.3)

Hypoxia‐inducible factors (HIFs) are transcriptional regulators that mediate hypoxic adaptation. We investigated the neuronal or glial cell‐specific role of HIF‐1α or HIF‐2α in the angiogenic adaptive response to chronic hypoxia by using the specific conditional knockout (KO) mice for HIF‐1α or HIF‐2α. The wild‐type (WT), conditional HIF‐1 KO (neuronal and glial) and conditional HIF‐2 KO mice (neuronal and glial) mice were exposed to the equivalent of 8% oxygen for 3 weeks in a hypobaric chamber at a pressure of 300 torr (0.4 ATM). Littermates of each type were kept normoxic in the same location. At the end of 3 weeks mice were perfusion‐fixed. Cerebral capillary density was identified from brain sections by GLUT‐1 immunohistochemistry staining and was quantified from the positive counts per unit area (number/mm2) in cortex. The normoxic baseline of capillary density was similar in the WT, neuronal HIF‐1 KO and the glial HIF‐2 KO mice (428 ± 66, 452 ± 54 and 440 ± 45, respectively, mean ±SD); the glial HIF‐1 KO and the neuronal HIF‐2 KO groups had higher normoxic baselines (483 ± 25 and 498 ± 55, respectively) than the WT mice. As expected, the capillary density was significantly increased by about 23% in the WT mice after 3 weeks of hypoxia, compared to that of their normoxic littermates. The capillary density was trended higher (about 10 to 15%) following hypoxia in the neuronal HIF‐1 KO, glial HIF‐1 KO and glial HIF‐2 KO groups; however, the capillary density remained unchanged in the neuronal HIF‐2 KO group. In addition, the hematocrit was similar in all groups before and after hypoxia. Or data suggest that HIF‐1 and HIF‐2 may regulate hypoxia‐induced angiogenesis differentially and cell‐specifically, and the neuronal HIF‐2 is required for hypoxic angiogenesis. Grant Funding Source : Supported by NIH grant NS 38362