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Papers In Press, published online ahead of print October 1, 2007
Molecular and Vascular Medicine, BIDMC, Harvard Medical School, Boston, MA 02215
Corresponding Author: rabid{at}bidmc.harvard.edu
Vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) play critical roles in vascular physiology and pathophysiology. We have previously demonstrated that NADPH oxidase-derived ROS are required for VEGF-mediated migration and proliferation of endothelial cells. The goal of the present study was to determine the extent to which VEGF signaling is coupled to NADPH oxidase activity. Human umbilical vein endothelial cells and/or human coronary artery endothelial cells were transfected with siRNA against the p47phox subunit of NADPH oxidase, treated in the absence or presence of VEGF, and assayed for signaling, gene expression and function. We show that NADPH oxidase activity is required for VEGF activation of PI3K-Akt-forkhead, and p38 MAPK, but not ERK1/2 or JNK. The permissive role of NADPH oxidase on PI3K-Akt-forkhead signaling is mediated at post-VEGF receptor level, and involves the non-receptor tyrosine kinase Src. DNA microarrays revealed the existence of two distinct classes of VEGF responsive genes, one that is ROS-dependent and another that is independent of ROS levels. VEGF-induced, thrombomodulin-dependent activation of protein C was dependent on NADPH oxidase activity, whereas VEGF-induced decay accelerating factor-mediated protection of endothelial cells against complement-mediated lysis was not. Taken together, these findings suggest that NADPH oxidase-derived ROS selectively modulate some but not all the effects of VEGF on endothelial cell phenotype.
J. Biol. Chem, 10.1074/jbc.M702175200
Submitted on March 13, 2007
Revised on September 24, 2007
Accepted on October 1, 2007
NADPH oxidase activity selectively modulates vascular endothelial growth factor signaling pathways
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