Vascular Endothelial Cell Growth Factor Attenuates Actions of Transforming Growth Factor-β in Human Endothelial Cells

Abstract Because vascular endothelial cell growth factor (VEGF) and transforming growth factor-β (TGF-β) are both involved in cellular growth and differentiation, we examined whether VEGF modifies TGF-β 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-β, was strongly enhanced (3.5-fold) by TGF-β treatment. Remarkably, physiological concentration of VEGF (30 nm) profoundly (by 60%) attenuated the TGF-β 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-β-stimulation of transcription of PAI-1 was clearly (by 60%) inhibited by VEGF. TGF-β phosphorylation of Smad2/3, an obligatory step of intracellular TGF-β signaling, was also suppressed by VEGF. VEGF attenuation of TGF-β action was also demonstrated in two other endothelial cell lines. In conclusion, VEGF attenuates TGF-β action in the human endothelial cell, specifically at the level of transcription of PAI-1 gene and Smad2/3 phosphorylation.