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 A2, a downstream metabolite of prostaglandin H synthase, in angiogenesis. A TXA2 mimetic, U46619, stimulated endothelial cell migration. Angiogenic basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) increased TXA2 synthesis in endothelial cells three- to fivefold. Inhibition of TXA2 synthesis with furegrelate or CI reduced HUVEC migration stimulated by VEGF or bFGF. A TXA2 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 TXA2 in angiogenesis and development of tumor metastasis.
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