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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2847-2853.
Prepublished online as a Blood First Edition Paper on November 21, 2006; DOI 10.1182/blood-2006-08-039743.
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Submitted August 4, 2006
Accepted November 10, 2006
Gene expression profiles identify a role for cyclooxygenase 2-dependent prostanoid generation in BMP6-induced angiogenic responses
Rongqin Ren, Peter C. Charles, Chunlian Zhang, Yaxu Wu, Hong Wang, and Cam Patterson*
Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
Dept of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
* Corresponding author; email: cpatters{at}med.unc.edu.
The bone morphogenetic protein (BMP) family of proteins participates in regulation of angiogenesis in physiological and pathological 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 upregulated by BMP stimulation, suggesting a role for Cox2 as a downstream regulator of BMP-induced angiogenesis. Upregulation 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 upregulated 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 of disparate pathways to modulate angiogenic responses in diseases in which neovascularization plays an underlying pathophysiologic role.
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