PATTERNS OF BRAIN ANGIOGENESIS AFTER VASCULAR ENDOTHELIAL GROWTH-FACTOR ADMINISTRATION IN-VITRO AND IN-VIVO

Vascular endothelial growth factor (VEGF) is a secreted endothelial ce ll mitogen that has been shown to induce vasculogenesis add angiogenes is in many organ systems and tumors. Considering the importance of VEG F to embryonic vascularization and survival, the effects of administer ed VEGF on developing or adult cerebrovasculature are unknown: can VEG F alter brain angiogenesis or mature cerebrovascular patterns? To exam ine these questions we exposed fetal, newborn, and adult rat cortical slice explants to graduated doses of recombinant VEGF. The effects of another known angiogenic factor, basic fibroblast growth factor (bFGF) , were evaluated in a comparable manner. In addition, we infused VEGF via minipump into the adult cortex. Significant angiogenic effects wer e found in all VEGF experiments in a dose-responsive manner that were abolished by the addition of VEGF neutralizing antibody. Fetal and new born explants had a highly complex network of branched vessels that im munoexpressed the flt-1 VEGF receptor, and flk-1 VEGF receptor express ion was determined by reverse transcription-PCR, Adult explants had en larged, dilated vessels that appeared to be an expansion of the existi ng network. All bFGF-treated explants had substantially fewer vascular profiles. VEGF infusions produced both a remarkable localized neovasc ularization and, unexpectedly, the expression of flt-1 on reactive ast rocytes but not on endothelial cells. The preponderance of neovascular ization in vitro and in vivo, however, lacked the blood-brain barrier (BBB) phenotype marker, GLUT-1, suggesting that in brain the angiogeni c role of VEGF may differ from a potential BBB functional role, i.e., transport and permeability. VEGF may serve an important capacity in ne ovascularization or BBB alterations after brain injury.