ROLE OF ADENOSINE IN THE HYPOXIC INDUCTION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IN PORCINE BRAIN-DERIVED MICROVASCULAR ENDOTHELIAL-CELLS (VOL 5, PG 155, 1997)

Hypoxia induced the mRNA expression of vascular endothelial growth fac tor (VEGF) in porcine brain derived microvascular endothelial cells (B MEC) in a time-dependent manner, Corresponding to the mRNA induction t he protein level of VEGF was elevated during hypoxia. The adenosine A( 1) receptor antagonist 8-phenyltheophylline (8-PT) reduced the hypoxia -induced VEGF mRNA and protein expression significantly. The treatment of BMEC with cobalt chloride-known to activate an oxygen sensing mech anism similar to the one used by the erythropoietin gene-also induced the VEGF mRNA expression, but 8-PT did not reduce this VEGF induction, Although, earlier studies revealed that agents like phorbolester indu ced the VEGF mRNA expression, the specific inhibitor of the proteinkin ase C (PKC) bisindolylmaleimide (BIM) did not reduce but enhanced the hypoxia-induced VEGF mRNA expression. These results indicate that the VEGF induction in BMEC can proceed through PKC-dependent and -independ ent pathways (like those acting via the putative oxygen sensor). Hypox ia in BMEC probably activates the PKC-dependent pathway mainly via ade nosine which might be formed during hypoxia and thereby inhibits activ ation of PKC-independent, oxygen sensing, pathways. This suggestion wa s supported by the fact that hypoxia as well as adenosine increased th e VEGF mRNA expression post-transcriptionally by enhancing the stabili ty of the VEGF mRNA.