Halima Rakhila1, Mahera Al-Akoum1, Charles Doillon1, Nicolas Lacroix-Pépin1, Mathieu Leboeuf1, Madeleine Lemyre1, Ali Akoum1, Marc Pouliot1. 1. Laboratory of Immunology (H.R., M.A.-A., C.D., M.P.), Research Center, Centre Hospitalier Universitaire de Québec, Faculty of Medicine, Laval University, Québec City, Canada; Laboratory of Reproduction (N.L.-P.), Faculty of Medicine, Laval University, Québec City, Canada; Department of Obstetrics and Gynecology (M. Leboueuf, M. Lemyre), Faculty of Medicine, Laval University, Québec City, Canada.
Abstract
CONTEXT: Angiogenesis is required for ectopic endometrial tissue growth. Our previous studies showed that prostaglandin F2α (PGF2α) biosynthetic enzymes and receptor were markedly elevated in endometriotic lesions and that PGF2α 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 PGF2αand exposed to agents that target PGF2α 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, PGF2α, vascular endothelial cell growth factor, and CXC chemokine ligand 8 mRNA and protein; FP prostanoid receptor expression. RESULTS: PGF2α 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. PGF2α 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 PGF2α 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 PGF2α in endometriosis-associated angio-inflammatory changes.
CONTEXT: Angiogenesis is required for ectopic endometrial tissue growth. Our previous studies showed that prostaglandin F2α (PGF2α) biosynthetic enzymes and receptor were markedly elevated in endometriotic lesions and that PGF2α 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 PGF2αand exposed to agents that target PGF2α 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, PGF2α, vascular endothelial cell growth factor, and CXC chemokine ligand 8 mRNA and protein; FP prostanoid receptor expression. RESULTS: PGF2α 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. PGF2α 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 PGF2α 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 PGF2α in endometriosis-associated angio-inflammatory changes.