Hypoxia‐induced angiogenesis is suppressed in COX‐2 deficient mouse brain cortex

Exposure to mild hypoxia induces angiogenesis in rat and mouse brain through cooperation of the HIF‐1 transcription factor‐vascular endothelial growth factor and the COX‐2‐angiopoietin 2 signaling pathways. To see if both systems were required for angiogenesis, 3 month old COX‐2 deficient mice (Jackson Laboratories) and their wild type littermates were exposed to the equivalent of 8% oxygen for 3 weeks in hypobaric chambers at a pressure of 300 torr (0.4 ATM). Littermate mice of each type were kept normoxic in the same location. At the end of 3 weeks the mice were perfused and fixed for immunohistochemical analyses. Brain capillaries were identified by glucose transporter, GLUT‐1, positive stain in 4 micron sections. Capillary density (N/mm 2 ) was estimated from 5 sections through the full depth of the parietal cortex of each mouse. As expected, hypoxic exposure increased the capillary density by about 20% in the wild‐type mice after 3‐weeks of hypoxia, compared to that of their normoxic littermates (416 ± 39 vs. 507 ± 41, mean ± SD, n = 3 each). However, the capillary density was unchanged COX‐2 −/− mice (401 ± 13 vs. 424 ± 24, mean ± SD, n = 3 each). In addition, there was no difference in the capillary density of COX‐2 −/− mice under normoxic conditions compared to their normoxic littermate controls. Our data suggest that the COX‐2 signaling pathway is required for cerebrovascular adaptation to prolonged mild hypoxia.