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Mechanisms of endothelial response to oxidative aggression: protective role of autologous VEGF and induction of VEGFR2 by H₂O₂

¹Laboratorio de Nefrología-Hipertensión, Fundación Jiménez Díaz; and ²Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain

Submitted 5 December 2005 ; accepted in final form 18 April 2006

The defense mechanisms of endothelial cells (EC) against reactive oxygen species (ROS) are insufficiently characterized. We have addressed the hypothesis that vascular endothelial growth factor (VEGF) and its receptors are relevant elements in this response. Cell viability, VEGF and VEGF receptor (VEGFR1 and VEGFR2) expression, and transcription factor activation were studied on transient exposure of monolayer EC to H₂O₂. Wild-type and mutant inhibitors of B (IB) constructions were used to further assess the role of NF-B in the induction of VEGFR2 expression. A concentration of H₂O₂ 60 µM elicited clear-cut damaging effects on EC, whereas lower concentrations (2–4 µM) were cytoprotective. The cytoprotective effect was shifted to an EC-damaging pattern by means of specific VEGF blockade, therefore revealing a major role of autologous VEGF. Exposure to H₂O₂ increased VEGF and VEGFR2 mRNA and protein in EC, without affecting VEGFR1 expression. Also, H₂O₂ challenge was accompanied by increased NF-B, activator protein-1, and specific protein-1 nuclear binding. A role of NF-B as the mediator of the H₂O₂ induction of VEGFR2 mRNA expression was supported by inhibition by the ROS scavenger pyrrolidine dithiocarbamate and by the blocking effect of transfected IB. Exposure to exogenous VEGF also increased VEGFR2 and induced NF-B in EC. In summary, autologous VEGF is instrumental for EC protection induced by low concentrations of ROS. ROS induce expression not only of VEGF but also of VEGFR2. VEGFR2 increase by ROS is mainly driven through a NF-B-dependent pathway.

cytoprotection; reactive oxygen species; vascular endothelial growth factor receptor; nuclear factor-b