Inhibition of TP signaling promotes endometriosis growth and neovascularization

Endometriosis is highly dependent on angiogenesis and lymphangiogenesis. Prostaglandin E(2), an arachidonic acid metabolite, has been shown to promote the formation of new blood and lymphatic vessels. However, the role of another arachidonic acid metabolite, thromboxane A(2) (TXA(2)) in angiogenesis and lymphangiogenesis during endometriosis remains largely unexplored. Using a murine model of ectopic endometrial transplantation, fragments from the endometrium of WT donor mice were transplanted into the peritoneal walls of recipient WT mice (WT→WT), resulting in an increase in both the area and density of blood and lymphatic vessels. Upon transplantation of endometrial tissue from thromboxane prostanoid (TP) receptor (TXA(2) receptor)-deficient (TP(−/−)) mice into TP(−/−) mice (TP(−/−)→TP(−/−)), an increase in implant growth, angiogenesis, and lymphangiogenesis were observed along with upregulation of pro-angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs). Similar results were obtained using a thromboxane synthase (TXS) inhibitor in WT→WT mice. Furthermore, TP(−/−)→TP(−/−) mice had a higher number of F4/80(+) cells than that of WT→WT mice, with increased expression of genes related to the anti-inflammatory macrophage phenotype in endometrial lesions. In cultured bone marrow (BM)-derived macrophages, the levels of VEGF-A, VEGF-C, and VEGF-D decreased in a TP-dependent manner. Furthermore, TP signaling affected the polarization of cultured BM-derived macrophages to the anti-inflammatory phenotype. These findings imply that inhibition of TP signaling promotes endometrial implant growth and neovascularization.