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J. Biol. Chem., Vol. 279, Issue 11, 10331-10337, March 12, 2004

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Ras Induction of Superoxide Activates ERK-dependent Angiogenic Transcription Factor HIF-1 and VEGF-A Expression in Shock Wave-stimulated Osteoblasts^*

Feng-Sheng Wang, Ching-Jen Wang, Yeung-Jen Chen¶, Per-Rong Chang||, Yu-Ting Huang, Yi-Chih Sun, Hueng-Chen Huang, Ya-Ju Yang, and Kuender D. Yang**

From the Department of Medical Research, Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan, Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, ^¶Department of Othopedic Surgery, Chang Gung University, Linkou 244, Taiwan, and ^||Fooyin University, Ta-Liau 831, Kaohsiung, Taiwan

Vascular endothelial growth factor (VEGF) released by osteoblasts plays an important role in angiogenesis and endochondral ossification during bone formation. In animal studies, we have reported that shock waves (SW) can promote osteogenic differentiation of mesenchymal stem cells through superoxide-mediated signal transduction (Wang, F. S., Wang, C. J., Sheen-Chen, S. M., Kuo, Y. R., Chen, R. F., and Yang, K. D. (2002) J. Biol. Chem. 277, 10931–10937) and vascularization of the bone-tendon junction. Here, we found that SW elevation of VEGF-A expression in human osteoblasts to be mediated by Ras-induced superoxide and ERK-dependent HIF-1 activation. SW treatment (0.16 mJ/mm², 1 Hz, 500 impulses) rapidly activated Ras protein (15 min) and Rac1 protein (30 min) and increased superoxide production in 30 min and VEGF mRNA expression in 6 h. Early scavenging of superoxide, but not nitric oxide, peroxide hydrogen, or prostaglandin E₂, reduced SW-augmented VEGF-A levels. Inhibition of superoxide production by diphenyliodonium, an NADPH oxidase inhibitor, was found to suppress VEGF-A expression. Transfection of osteoblasts with a dominant negative (S17N) Ras mutant abrogated the SW enhancement of Rac1 activation, superoxide synthesis, and VEGF expression. Further studies demonstrated that SW significantly promoted ERK activation in 1 h and HIF-1 phosphorylation and HIF-1 binding to VEGF promoter in 3 h. In support of the observation that superoxide mediated the SW-induced ERK activation and HIF-1 transactivation, we further demonstrated that scavenging of superoxide by superoxide dismutase and inhibition of ERK activity by PD98059 decreased HIF-1 activation and VEGF-A levels. Moreover, culture medium harvested from SW-treated osteoblasts increased vessel number of chick chorioallantoic membrane. Superoxide dismutase pretreatment and anti-VEGF-A antibody neutralization reduced the promoting effect of conditioned medium on angiogenesis. Thus, modulation of redox reaction by SW may have some positive effect on angiogenesis during bone regeneration.

Received for publication, July 23, 2003 , and in revised form, December 15, 2003.

^* This work was supported in part by Grant NHRI-EX92-9128EI from the National Health Research Institute, Taiwan (to F.-S. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed.: Dept. of Medical Research, Chang Gung Memorial Hospital, 123, Ta-Pei Rd., Niao-Sung, Kaohsiung 833, Taiwan. Tel.: 886-7-731-7123 (ext. 8876); E-mail: wangfs{at}ms33.hinet.net.

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