COX-2 limits prostanoid production in activated HUVECs and is a source of PGH2 for transcellular metabolism to PGE2 by tumor cells.
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.


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 PGE(2) synthase (PGES) activity. Endothelial PGE(2) production is partly mediated by nonenzymatic decomposition of COX-2-derived PGH(2), but endothelial-produced PGH(2) can also be metabolized enzymatically by microsomal PGES-1 in cocultured tumor cells.


CONCLUSIONS
Our findings identify a novel transcellular metabolism of PGE(2) between the endothelial and tumor compartments. Given the role of PGE(2) as a mediator of COX-2 proangiogenic effects, transcellular metabolism of endothelial-derived PGH(2) is a potential target for treatment of pathological angiogenesis.
Salvado
M Dolores
MD
Department of Vascular Biology and Inflammation, Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Alfranca
Arántzazu
A
Escolano
Amelia
A
Haeggström
Jesper Z
JZ
Redondo
Juan Miguel
JM
D045744:Cell Line, Tumor; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000502:physiology*; D015232:Dinoprostone / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000502:physiology; D044262:Prostaglandin H2 / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D053583:Interleukin-1beta; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D044262:Prostaglandin H2; D051546:Cyclooxygenase 2; D015232:Dinoprostone