INCREASED GENE-EXPRESSION FOR VEGF AND THE VEGF RECEPTORS KDR FLK ANDFLT IN LUNGS EXPOSED TO ACUTE OR TO CHRONIC HYPOXIA - MODULATION OF GENE-EXPRESSION BY NITRIC-OXIDE/

Endothelial cells constitute an essential integrator of factors that a ffect blood vessel remodeling induced by chronic hypoxia, We hypothesi zed that vascular endothelial growth factor (VEGF) may participate in the lung response to acute and to chronic hypoxia, We found that ex vi vo perfusion of isolated lungs under hypoxic conditions (when compared with normoxia) caused an increase in lung tissue mRNA of VEGF and of the VEGF receptors KDR/Flk and Fit, Chronic hypobaric hypoxia also inc reased lung tissue mRNA levels of VEGF, KDR/Flk, and Fldt and the amou nt of VEGF protein, In situ hybridization studies demonstrated increas ed VEGF and KDR/flk hybridization signals in lungs from chronically hy poxic rats, Since endotoxin treatment of rats decreased lung VEGF mRNA , we postulated that nitric oxide (NO) or an NO-related metabolite mig ht be involved in lung VEGF gene expression, Indeed, sodium nitropruss ide, a NO donor, decreased and L-NAME (N-nitro-L-arginine methyl ester ), an inhibitor of NO-synthesis, increased both VEGF and VEGF receptor transcripts, We conclude that VEGF in the isolated perfused lung acts as an early gene in response to hypoxia and that lung VEGF and VEGF r eceptor mRNA levels are influenced by hypoxia and NO-dependent mechani sms.