Regulation of prostanoid biosynthesis by human endothelial cells in angiogenesis : role of cox-2 in the intracellular and transcellular synthesis of prostanoids
Author
Salvado Duro, María DoloresEntity
UAM. Departamento de Biología MolecularDate
2008-10-24Subjects
Biosíntesis - Tesis doctorales; Vasos sanguíneos - Tesis doctorales; Ácido eicosanoide - Derivados - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 24-10-2008Abstract
In the past several years, prostanoids have emerged as key regulators of angiogenesis in
carcinoma and chronic inflammatory disease progression. In addition, recent reports
have indicated that neo-angiogenesis requires an up-regulation of prostanoid
biosynthetic enzymes. Thus, an induced expression of COX-2 and several tPGSs (eg.
mPGES-1, TXAS) has been observed in cancer, stromal and inflammatory cells (eg.
macrophages), in which the ability to synthesize prostanoids has been extensively
studied. However, very little is known about the prostanoid synthesis by the vascular
compartment, which plays an essential role in the angiogenic process. Therefore, in the
present study, we characterize the profile of prostanoid production in endothelial cells
upon treatment with proangiogenic and proinflammatory cytokines, and analyzed the
expression of the endothelial terminal prostanoid synthases of PGE2, PGI2 and TXA2 in
this angiogenic context. HUVEC were treated with either VEGF or IL-1β, and
prostanoid contents in cell supernatants determined by enzyme-immunoassay, showing
an up-regulated PGE2, PGI2 and TXA2 production. However, none concomitant upregulated
expression nor enzymatic activation of the corresponding terminal prostanoid
synthases was observed in endothelial cells. Our results indicate a major role of COX-2
in the biosynthesis of endothelial prostanoids. On the one hand, we have observed how
the levels of prostanoids increased concomitantly to the induced expression of COX-2,
on the other, this was confirmed by the fact that COX-2 silencing or selective inhibition
was the only condition that significantly affected prostanoid (PGE2, PGI2, TXA2) levels
in endothelial cells under both resting or stimulating conditions, thus hightlighting a
preferential functional coupling of endothelial terminal prostanoid synthases to COX-2.
Furthermore, COX-2 also up-regulates PGH2 production, which can be untransformed
released by endothelium, and taken up and metabolized by mPGES-1 of the
neighbouring tumor cells, present at the angiogenic scenario. To our knowlegde, this is
the first report of eicosanoid/PGE2 production induced by the transcellular metabolism
through the tumor-endothelium cross-talk during angiogenesis. A role for endothelialderived
PGH2 should be considered in the design of new therapeutical approches in
pathological angiogenesis.
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