Inhibition of VEGFR1 TK Signaling in Peritoneal Macrophages Suppresses Endometriosis Development.

BACKGROUND/AIM: Endometriosis is characterized by the accumulation of immune cells in endometrial lesions and the peritoneal cavity. Macrophages contribute to the growth and neovascularization of endometriotic lesions. Vascular endothelial growth factor receptor-1 (VEGFR1) is involved in neovascularization, while peritoneal macrophages (PMs) play a critical role in endometriosis development and establishment. We examined the role of VEGFR1 signaling in PMs during endometriosis development using a murine model of ectopic endometrial transplantation.

MATERIALS AND METHODS

Endometrial fragments from female wild-type (WT) or VEGFR1 tyrosine kinase-deficient (TK) donor mice were implanted into the peritoneal walls of recipient mice, either in a WT→WT or TK→TK combination. On day 14 after endometrial transplantation, the implant size, neovascular growth-promoting factors, macrophage accumulation in the implants and peritoneal cavity, and cytokine production were assessed. PMs from WT or TK mice were transferred into the peritoneal cavity of WT→WT mice and their effects were assessed.

RESULTS

Compared to WT→WT mice, TK→TK mice exhibited smaller implant sizes and reduced neovascularization, including angiogenesis and lymphangiogenesis. This was correlated with an increase in pro-inflammatory (M1) and a decrease in alternative (M2) large peritoneal macrophages (LPMs) within the peritoneal cavity. Transfer of TK-PMs into the peritoneal cavity of WT→WT mice reduced endometriosis development and macrophage accumulation. This led to increased expression of M1 macrophage genes and decreased expression of M2 phenotype genes, compared to WT-PMs transfer. PMs from TK mice exhibited increased M1-related and decreased M2-related gene expression.

CONCLUSION

Deletion of VEGFR1 TK signaling in PMs suppressed endometriosis progression and neovascularization by increasing M1 LPMs. Specific inactivation of VEGFR1 TK signaling may represent a potential therapeutic target for the management of endometriosis.