Angiopoietin-2 and rat brain capillary remodeling during adaptation and deadaptation to prolonged mild hypoxia

Angiogenesis is a crucial component of rat brain adaptation to prolonged hypoxia, but it is not known whether this structural change is permanent or reversed on return to normoxia. Also, the intrinsic mechanisms controlling brain microvascular plasticity in response to oxygen availability remains unclear. Our results indicate that capillary density in the rat cerebral cortex increased by 60% after 3 wk of hypoxia and that it progressively decreased to prehypoxic values after 3 wk of normoxic recovery (deadaptation). Angiopoietin-2 (Ang2) expression in the capillary endothelium was induced between 6 h and 14 days of hypoxia but fell to control levels at 21 days of hypoxia. During deadaptation, Ang2 levels were elevated at 1-14 days but decreased to baseline at 21 days. In contrast, the constitutive expression of Ang1 and Tie2 was not affected during hypoxia or deadaptation. TUNEL-positive endothelial cells and caspase-3 activation were observed at 7 and 14 days of deadaptation. These data suggest that Ang2 might modulate both angiogenesis and vascular regression in the rat brain and that capillary regression occurring during deadaptation involves activation of apoptosis.