Nox1 Mediates Basic Fibroblast Growth Factor-Induced Migration of Vascular Smooth Muscle Cells

Abstract

Objectives-Basic fibroblast growth factor (bFGF) stimulates vascular smooth muscle cell (SMC) migration. We determined whether bFGF increases SMC reactive oxygen-species (ROS) and studied the role of ROS for SMC migration. Methods and Results-bFGF rapidly increased rat SMC ROS formation and migration through pathways sensitive to inhibition of NADPH oxidases, PI3-kinase, protein kinase C, and Rac-1. SiRNA directed against the NADPH oxidase Nox4 impaired basal but not bFGF-induced ROS formation and did not affect migration. In contrast, siRNA against Nox1 blocked the agonist-induced ROS generation as well as the bFGF-induced migration. Agonist-induced migration was also attenuated in SMC derived from Nox1 y/Ϫ mice and transduction of Nox1 restored normal migration. Likewise, SMC outgrowth in response to bFGF was attenuated in aortic segments from Nox1 y/Ϫ mice as compared with Nox1 y/ϩ mice. bFGF activated JNK but not Src in a Nox1-dependent manner. Consequently, phosphorylation of the adaptor protein paxillin, which is central for migration and secretion of matrix-metalloproteinases, were dependent on Nox1 as well as JNK but not Src. Conclusions-These

NADPH Oxidase 1 Controls the Persistence of Directed Cell Migration by a Rho-Dependent Switch of α2/α3 Integrins

“…Many reports showed, by using pharmacological inhibition, that ROS produced through an NADPH oxidase-like complex affect cell migration (23,49). Recent molecular evidence for the involvement of Nox/Duox homologues in the control of cell migration has been reported for Nox2 in endothelial cells (45,54), Nox1 in vascular smooth muscle cells and colonic epithelial cells (38,40), Nox4 in myofibroblast and vascular smooth muscle cells (15,16,28), and Duox1 in airway epithelial cells (49). In a previous report, we showed that Nox1 controls colonic epithelial cell migration on Col-I by modulating ␣2 integrin membrane availability.…”

“…Abrogation of Nox1-dependent ROS production by diphenyleneiodonium (DPI) or small interfering RNA restores RhoA activation and actin stress fiber formation (41). More recently, several groups have highlighted a key role of Nox1 in the control of growth factorinduced migration (16,38,40). Cancer cells probably undergo random migration during metastasis, but their migration can be directed by cytokine gradients and/or associated with ECM fibers (29,55).…”

CD44-Epidermal Growth Factor Receptor Interaction Mediates Hyaluronic Acid-promoted Cell Motility by Activating Protein Kinase C Signaling Involving Akt, Rac1, Phox, Reactive Oxygen Species, Focal Adhesion Kinase, and MMP-2

“…ROS mediated fibroblast migration by increasing phosphorylation of Cortactin (22). In addition, ROS mediated growth factor-induced migration of vascular smooth muscle cells (23).…”

Nox4 Oxidase Overexpression Specifically Decreases Endogenous Nox4 mRNA and Inhibits Angiotensin II–Induced Adventitial Myofibroblast Migration

“…4,5,19,20 Nox1 upregulation has been postulated to promote vascular cell proliferation and migration during restenosis. 20 Schröder et al 21 reported recently that migration of vascular smooth muscle cells induced by fibroblast growth factor is mediated by Nox1. We reported that the vascular adventitia expresses the Nox2-based oxidase system, which is involved in the production of O 2 Ϫ by adventitial fibroblasts 22,23 and neointimal hyperplasia, 5,24 with the latter process being partially attributed to the migration of adventitial myofibroblasts.…”