Vascular endothelial cell growth factor attenuates actions of transforming growth factor-beta in human endothelial cells.
Because vascular endothelial cell growth factor (VEGF) and transforming growth factor-beta (TGF-beta) are both involved in cellular growth and differentiation, we examined whether VEGF modifies TGF-beta signaling cascade in human umbilical cord vein endothelial cells (HUVEC). Production of plasminogen activator inhibitor-1 (PAI-1), which is under the specific control of TGF-beta, was strongly enhanced (3.5-fold) by TGF-beta treatment. Remarkably, physiological concentration of VEGF (30 nm) profoundly (by 60%) attenuated the TGF-beta stimulation of PAI-1 production without an effect on the basal PAI-1 production. In HUVECs transiently transfected with an expression construct containing a PAI-1 promoter fused to luciferase reporter gene, TGF-beta-stimulation of transcription of PAI-1 was clearly (by 60%) inhibited by VEGF. TGF-beta phosphorylation of Smad2/3, an obligatory step of intracellular TGF-beta signaling, was also suppressed by VEGF. VEGF attenuation of TGF-beta action was also demonstrated in two other endothelial cell lines. In conclusion, VEGF attenuates TGF-beta action in the human endothelial cell, specifically at the level of transcription of PAI-1 gene and Smad2/3 phosphorylation.
Yamauchi
Keishi
K
Department of Aging Medicine and Geriatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
Nishimura
Yoshihiro
Y
Shigematsu
Satoshi
S
Takeuchi
Yuichiro
Y
Nakamura
Junko
J
Aizawa
Toru
T
Hashizume
Kiyoshi
K
D000730:Androstadienes / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014470:Umbilical Cord / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology*; D000077191:Wortmannin
D000730:Androstadienes; D004268:DNA-Binding Proteins; D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D008156:Luciferases; D000077191:Wortmannin