Thromboxane A2 Regulation of Endothelial Cell Migration, Angiogenesis, and Tumor Metastasis☆

Abstract Prostaglandin endoperoxide H synthases and their arachidonate products have been implicated in modulating angiogenesis during tumor growth and chronic inflammation. Here we report the involvement of thromboxane A 2 , a downstream metabolite of prostaglandin H synthase, in angiogenesis. A TXA 2 mimetic, U46619, stimulated endothelial cell migration. Angiogenic basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) increased TXA 2 synthesis in endothelial cells three- to fivefold. Inhibition of TXA 2 synthesis with furegrelate or CI reduced HUVEC migration stimulated by VEGF or bFGF. A TXA 2 receptor antagonist, SQ29,548, inhibited VEGF- or bFGF-stimulated endothelial cell migration. In vivo, CI inhibited bFGF-induced angiogenesis. Finally, development of lung metastasis in C57Bl/6J mice intravenously injected with Lewis lung carcinoma or B16a cells was significantly inhibited by thromboxane synthase inhibitors, CI or furegrelate sodium. Our data demonstrate the involvement of TXA 2 in angiogenesis and development of tumor metastasis.