Augmented Angiogenic Factors Expression via FP Signaling Pathways in Peritoneal Endometriosis.

Abstract

Angiogenesis is required for ectopic endometrial tissue growth. Our previous studies showed that prostaglandin F_2α (PGF_2α) biosynthetic enzymes and receptor were markedly elevated in endometriotic lesions and that PGF_2α is a potent angiogenic factor in endothelial cells. We sought to determine whether or not the F-prostanoid receptor modulates angiogenesis in ectopic stromal cells. Release of angiogenic factors by ectopic endometrial stromal cell primary cultures stimulated with PGF_2αand exposed to agents that target PGF_2α signaling was assessed. The study was conducted in an immunology laboratory at the Centre Hospitalier Universitaire (Québec City) medical research center. Women found to have peritoneal endometriosis during laparoscopy were included in this study. Prostaglandin E₂, PGF_2α, vascular endothelial cell growth factor, and CXC chemokine ligand 8 mRNA and protein; FP prostanoid receptor expression. PGF_2α markedly up-regulated prostaglandin E₂, CXC chemokine ligand 8 and vascular endothelial cell growth factor secretion in endometriotic cells. This effect was suppressed in the presence of a specific F-prostanoid antagonist (AL8810) and its signaling pathway was dependent on F-prostanoid receptor variant. PGF_2α can exert its proliferative and angiogenic activities either directly by stimulating endothelial cell proliferation, migration and angiogenesis through F-prostanoid receptor, or indirectly, by stimulating endometriotic stromal cells to produce potent angiogenic factors through either receptor variant. These results show for the first time that PGF_2α exerts an angiogenic effect on ectopic stromal cells, inducing the secretion of major angiogenic factors via different F-prostanoid signaling pathways. This study suggests a new interpretation of the mechanism underlying endometriosis development involving PGF_2α in endometriosis-associated angio-inflammatory changes.