Gene expression profiles identify a role for cyclooxygenase 2-dependent prostanoid generation in BMP6-induced angiogenic responses.
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.
Ren
Rongqin
R
Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill 27599-7126, USA.
Charles
Peter C
PC
Zhang
Chunlian
C
Wu
Yaxu
Y
Wang
Hong
H
Patterson
Cam
C
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015342:DNA Probes / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008833:Microcirculation / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011453:Prostaglandins / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
C525816:BMP6 protein, human; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D052246:Cyclooxygenase 2 Inhibitors; D015342:DNA Probes; D011453:Prostaglandins; D011994:Recombinant Proteins; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2