O11	Nox1 mediates basic fibroblast growth factor-induced vascular smooth muscle cell migration.
K.Schroeder, A.Keller, R.Busse, R.P.Brandes
J.W. Goethe-Universität, Frankfurt/Main, DE.

Basic fibroblast growth factor (bFGF) is a potent activator of vascular smooth muscle cell (VSMC) migration that promotes neo-intima formation. Reactive oxygen species (ROS) have been suggested to play a key role for the development and progression of vascular disease. We determined whether bFGF increases ROS formation in VSMC and studied the underlying molecular mechanism. Furthermore we identified the role of bFGF-induced ROS formation for smooth muscle migration. bFGF rapidly increased ROS formation in rat and human VSMC via a mechanism sensitive to the specific NADPH oxidase inhibitors apocynin and gp91-ds-tat as well as to inhibition of PI3-kinase and Rac. Pre-treatment of VSMC with the NADPH oxidase inhibitor gp91ds-TAT also completely prevented the bFGF-induced activation of p38 MAP kinase and JNK. bFGF induced a marked migration of VSMC, which was blocked by PI3-kinase and Rac inhibitors. Moreover, antioxidants as well as the specific inhibition of the NADPH oxidase prevented migration. In order to determine the NADPH oxidase homologues responsible for bFGF-induced migration, siRNA against Nox homologues were used. bFGF-induced migration was completely blocked by siRNA directed against Nox1 but remained unaffected by Nox4 siRNA. These data demonstrate that bFGF activates the Nox1-containing NADPH oxidase via a pathway involving Rac and PI3-Kinase. Nox1-dependent ROS formation is critical for bFGF-induced signaling leading to VSMC migration.

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