Augmented Angiogenic Factors Expression via FP Signaling Pathways in Peritoneal Endometriosis

Abstract

Context: 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.

Objective: We sought to determine whether or not the F-prostanoid receptor modulates angiogenesis in ectopic stromal cells.

Design: 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.

Setting: The study was conducted in an immunology laboratory at the Centre Hospitalier Universitaire (Québec City) medical research center.

Patients: Women found to have peritoneal endometriosis during laparoscopy were included in this study.

Main outcome measure(s): Prostaglandin E₂, PGF_2α, vascular endothelial cell growth factor, and CXC chemokine ligand 8 mRNA and protein; FP prostanoid receptor expression.

Results: 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.

Conclusion: 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.