Induction of cyclooxygenase-1 and -2 modulates angiogenic responses to engagement of alphavbeta3.
Prostaglandins and cyclooxygenase (COX) have been implicated in the angiogenesis that occurs around tumours, but how they are induced is unclear. Prostaglandin formation is regulated by the availability of arachidonic acid and/or COX activity that in turn are controlled by activation of G-protein-coupled receptors or kinase receptors. Adhesion receptors provide another potential level of control as they transduce a variety of "outside-in" signals implicated in inflammation. We examined whether engagement of the vitronectin receptor (alphavbeta3) modulated prostacyclin (PGI2) formation in human umbilical vein endothelial cells (EC). Engagement of EC alphavbeta3 by vitronectin (versus fibronectin or gelatin) or by monoclonal antibodies (mAbs) LM609 and LIBS6, enhanced PGI2 generation and also induced expression of both COX-1 and -2 isoforms. Alphavbeta3 engagement also led to vascular endothelial cell growth factor (VEGF) generation and EC proliferation that was attenuated by inhibition of both COX-1 and COX-2. COX-1 inhibition also prevented new vessel formation in an in vitro model of angiogenesis that is alphavbeta3 dependent. Inhibition of angiogenesis by the COX-1 inhibitor was partially reversed by removal of the inhibitor or by addition of the stable analogue of PGI2, iloprost. These findings strongly indicate that alphavbeta3-mediated angiogenesis is partly due to induction of both isoforms of COX.
Murphy
Joseph F
JF
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, Ireland. jmurphy@rcsi.ie
Steele
Christopher
C
Belton
Orina
O
Fitzgerald
Desmond J
DJ
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002455:Cell Division; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000201:enzymology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism; D005353:Fibronectins / Q000494:pharmacology; D005780:Gelatin / Q000494:pharmacology; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D039302:Integrin alphaVbeta3 / Q000276:immunology / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008222:Lymphokines / Q000096:biosynthesis; D008565:Membrane Proteins; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019096:Vitronectin / Q000378:metabolism / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D005353:Fibronectins; D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D011720:Pyrazoles; C115461:SC 560; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019096:Vitronectin; D005780:Gelatin; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D016285:Iloprost