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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 2α and 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 E 2 , 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 E 2 , 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.