Astrocyte-derived VEGF mediates survival and tube stabilization of hypoxicbrain microvascular endothelial cells in vitro

Chronic sublethal hypoxia has been associated with changes in neurovascular behavior, mediated, in part, by induction of vascular endothelial growth f actor-A (VEGF-A(165)). In this report we demonstrate that RBE4 cells (deriv ed from rodent cerebral microvasculature), when cultured in three-dimension al collagen gels: (1) Are induced to undergo increased tube formation in re sponse to VEGF-A(165) in a dose-dependent manner; (2) undergo apoptosis und er mild hypoxic conditions; (3) are rescued from the effects of hypoxia by the addition of exogenous VEGF-A(165) in a dose-dependent and inhibitable m ariner or by co-culture with primary newborn rat astrocytes, which are indu ced to express increased amounts of VEGF-A in hypoxic conditions. Further, we demonstrate that: (4) The observed astrocyte produced, VEGF-mediated pro tection from apoptosis (survival) is inhibitable with soluble recombinant V EGF receptor-1 (sFlt), and is associated with a robust induction of MAPK ty rosine phosphorylation. These findings illustrate the importance of VEGF in the process of neurovascular survival in response to injury in developing brain and provide insight into the signaling pathways involved. (C) 2001 El sevier Science B.V. All rights reserved.