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The bone morphogenetic protein (BMP) family of proteins participates in regulation of angiogenesis in physiologic and pathologic conditions. To investigate the molecular mechanisms that contribute to BMP-dependent angiogenic signaling, we performed gene expression profiling of BMP6-treated mouse endothelial cells. We detected 77 mRNAs that were differentially regulated after BMP6 stimulation. Of these, cyclooxygenase 2 (Cox2) was among the most highly up-regulated by BMP stimulation, suggesting a role for Cox2 as a downstream regulator of BMP-induced angiogenesis. Up-regulation of Cox2 by BMP6 was detected at both mRNA and protein levels in endothelial cells, and BMP6 increased production of prostaglandins in a Cox2-dependent fashion. BMP6 up-regulated Cox2 at the transcriptional level through upstream SMAD-binding sites in the Cox2 promoter. Pharmacologic inhibition of Cox2, but not Cox1, blocked BMP6-induced endothelial cell proliferation, migration, and network assembly. BMP6-dependent microvessel outgrowth was markedly attenuated in aortic rings from Cox2−/− mice or after pharmacologic inhibition of Cox2 in aortas from wild-type mice. These results support a necessary role for Cox2 in mediating proangiogenic activities of BMP6. These data indicate that Cox2 may serve as a unifying component downstream from disparate pathways to modulate angiogenic responses in diseases in which neovascularization plays an underlying pathophysiologic role.