Lymphangiogenesis induced by vascular endothelial growth factor receptor 1 signaling contributes to the progression of endometriosis in mice

Kyoko Hattori, Yoshiya Ito, Masako Honda, Kazuki Sekiguchi, Kanako Hosono, Masabumi Shibuya, Nobuya Unno, Masataka Majima
Journal of pharmacological sciences · 2020 · vol. 143(4) , pp. 255–263 · doi:10.1016/j.jphs.2020.05.003 · PMID:32487450 · W3025093490
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Abstract

Lymphangiogenesis is related to the growth of endometriosis. Here, we examined whether vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) signaling plays a role in lymphangiogenesis during endometriosis. Endometrial fragments from wild-type (WT) mice transplanted into the peritoneal wall of host WT mice (WT→WT) developed well and displayed enhanced lymphangiogenesis associated with increases in mRNA levels of VEGF-C and VEGF-D. Compared with WT mice, the implant size and lymphangiogenesis were reduced, when endometrial fragments from mice lacking the VEGFR1 tyrosine kinase (TK) domain (TK-/-) were transplanted into host TK-/- mice (TK-/-→TK-/-). Treatment of WT→WT mice with the VEGFR3 kinase inhibitor suppressed the size of implants and lymphangiogenesis. Immunofluorescence analyses demonstrated that VEGF-C and VEGF-D were expressed in both CD11b+ and S100A4+ cells. TK-/-→TK-/- mice had lower numbers of CD11b+ and S100A4+ cells than WT→WT mice. When isolated bone marrow (BM)-derived macrophages or culture murine fibroblasts were stimulated with placental growth factor (PlGF), a specific agonist of VEGFR1, the levels of VEGF-C and VEGF-D were increased in a VEGFR1-dependent manner. These results suggest that VEGFR1 signaling in macrophages and fibroblasts contributes to the growth of endometrial implants and lymphangiogenesis.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Endometriosis Lymphangiogenesis Signal Transduction Vascular Endothelial Growth Factor Receptor-1 Animals Disease Progression Endometriosis Female Lymphangiogenesis Mice Mice, Inbred C57BL

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