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Reactive oxygen species production via NADPH oxidase mediates TGF--induced cytoskeletal alterations in endothelial cells

The Dorrance Hamilton Research Laboratories, ¹Division of Nephrology, ²Division of Endocrinology, Department of Medicine, ³Department of Physiology, Thomas Jefferson University, Philadelphia, Pennsylvania

Submitted 21 January 2005 ; accepted in final form 6 May 2005

Cytoskeletal alterations in endothelial cells have been linked to nitric oxide generation and cell-cell interactions. Transforming growth factor (TGF)- has been described to affect cytoskeletal rearrangement in numerous cell types; however, the underlying pathway is unclear. In the present study, we found that human umbilical vein endothelial cells (HUVEC) have marked cytoskeletal alterations with short-term TGF- treatment resulting in filipodia formation and F-actin assembly. The cytoskeletal alterations were blocked by the novel TGF- type I receptor/ALK5 kinase inhibitor (SB-505124) but not by the p38 kinase inhibitor (SB-203580). TGF- also induced marked stimulation of reactive oxygen species (ROS) within 5 min of TGF- exposure. TGF- stimulation of ROS was mediated by the NAPDH oxidase homolog Nox4 as DPI, an inhibitor of NADPH oxidase, and dominant-negative Nox4 adenovirus blocked ROS production. Finally, inhibition of ROS with ROS scavengers or dominant-negative Nox4 blocked the TGF- effect on cytoskeleton changes in endothelial cells. In conclusion, our studies show for the first time that TGF--induced ROS production in human endothelial cells is via Nox4 and that TGF- alteration of cytoskeleton in HUVEC is mediated via a Nox4-dependent pathway.

human umbilical vein endothelial cells; cell-cell interactions; cytoskeletal rearrangement; transforming growth factor-

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