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Published Online
on May 7, 2009

Arteriosclerosis, Thrombosis, and Vascular Biology. 2009
Published online before print May 7, 2009, doi: 10.1161/ATVBAHA.109.188540
A more recent version of this article appeared on July 1, 2009
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Submitted on October 16, 2008
Accepted on April 19, 2009

COX-2 Limits Prostanoid Production in Activated HUVECs and Is a Source of PGH2 for Transcellular Metabolism to PGE2 by Tumor Cells

M. Dolores Salvado ; Arántzazu Alfranca ; Amelia Escolano ; Jesper Z. Haeggström ; and Juan Miguel Redondo *

From the Department of Vascular Biology and Inflammation (M.D.S., A.A., A.E., J.M.R.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; the Department of Medical Biochemistry and Biophysics, Division of Chemistry 2 (J.Z.H.), Karolinska Institutet, Stockholm, Sweden.

* To whom correspondence should be addressed. E-mail: jmredondo{at}cnic.es.

Objective—Inducible expression of cyclooxygenase-2 (COX-2) and terminal prostaglandin synthases (tPGS) has been mainly analyzed in tumor, stromal, and inflammatory cells, and little is known about the regulation of prostanoid biosynthesis by endothelial cells. Here we characterize the profile of prostanoids produced by activated HUVECs and analyze the expression and activities of tPGS.

Methods and Results—Enzyme immunoassays indicated increased endothelial prostanoid production after proangiogenic stimulation, but without parallel upregulation of tPGS. Endothelial prostanoid production instead depended on the induction of COX-2 and was abolished by COX-2 silencing or pharmacological inhibition. COX-2 is functionally coupled to prostacyclin and thromboxane synthases in HUVECs, but these cells show no detectable PGE2 synthase (PGES) activity. Endothelial PGE2 production is partly mediated by nonenzymatic decomposition of COX-2-derived PGH2, but endothelial-produced PGH2 can also be metabolized enzymatically by microsomal PGES-1 in cocultured tumor cells.

Conclusions—Our findings identify a novel transcellular metabolism of PGE2 between the endothelial and tumor compartments. Given the role of PGE2 as a mediator of COX-2 proangiogenic effects, transcellular metabolism of endothelial-derived PGH2 is a potential target for treatment of pathological angiogenesis.




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