Prolonged hypoxia increases vascular endothelial growth factor mRNA and protein in adult mouse brain

Brain hypoxia induces an increase in brain vascularity, presumably mediated by vascular endothelial growth factor (VEGF), but it is unclear whether VE GF is required to maintain the increase. In these studies, brain VEGF mRNA and protein levels were measured in adult mice kept in hypobaric chambers a t 0.5 atm for 0, 0.5, 1, 2, 4, 7, and 21 days. Hypoxia was accompanied by a transient increase of VEGF mRNA expression: twofold by 0.5 day and a maxim um of fivefold by 2 days; these were followed by a decrease at 4 days and a return to basal levels by 7-21 days. VEGF protein expression induced by hy poxia was bimodal, initially paralleling VEGF mRNA. There was an initial sm all increase at 12 h that reached a maximum by day 2, and, after a transien t decrease on day 4, the protein expression increased again on day 7 before it returned to normoxic levels after 21 days. Thus, despite continued hypo xia, both VEGF mRNA and protein levels returned to basal after 7 days. Thes e data suggest a metabolic negative-feedback system for VEGF expression dur ing prolonged hypoxia in the brain.