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Papers In Press, published online ahead of print December 16, 2003
Department of Medical Research, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Kaohsiung 833
Corresponding Author: wangfs{at}ms33.hinet.net
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 (J. Biol. Chem. 277:10931-1937; 2002) and vascularization of 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-1alpha activation. SW treatment (0.16 mJ/mm2, 1 Hz, 500 impulses) rapidly activated Ras protein and Rac1 protein, increased superoxide production in 30 min and VEGF m RNA expression in 6 hours. Early scavenging of superoxide 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 hour, and HIF-1alpha phosphorylation and HIF-1alphabinding to VEGF promoter in 3 hours. We further demonstrated that scavenging of superoxide by SOD and inhibition of ERK activity by PD98059 decreased HIF-1alpha activation and VEGF-A levels. Culture medium harvested from SW-treated osteoblasts increased vessel number of chick chorioallantoic membrane (CAM). SOD pretreatment and anti-VEGF-A antibody neutralization reduced SW-promoted blood vessel formation of CAM. Taken together, we have showed that SW induced Ras and Rac1 activation followed by superoxide-mediated ERK and HIF-1alpha activation resulted in an increase of VEGF expression and angiogenesis in vivo.
J. Biol. Chem, 10.1074/jbc.M308013200
Submitted on July 23, 2003
Revised on December 15, 2003
Accepted on December 16, 2003
Ras modulation of superoxide activates ERK-dependent angiogenic transcription (HIF-1alpha) and VEGF-A expression in shock wave-stimulated osteoblasts
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