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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1131.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

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; 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.

Correspondence to Juan Miguel Redondo and Arántzazu Alfranca, Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares. Melchor Fernández Almagro, 3. 28029 Madrid, Spain. E-mail jmredondo{at}cnic.es or aalfranca@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.

Upregulated prostanoid production by activated endothelial cells is limited by COX-2, which is functionally coupled to endothelial PGIS and TXAS. Endothelial COX-2 regulates the release of untransformed PGH₂, which can either undergo nonenzymatic rearrangement or be enzymatically converted into PGE₂ through a transcellular mechanism by tumor-cell mPGES-1.

Key Words: angiogenesis • endothelium • cyclooxygenases • prostanoids • transcellular metabolism

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