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.

淋巴管生成与子宫内膜异位症的生长有关。在这里，我们检查了血管内皮生长因子（VEGF）受体1（VEGFR1）信号在子宫内膜异位症的淋巴管生成中是否起作用。来自野生型（WT）小鼠的子宫内膜碎片移植到宿主WT小鼠（WT→WT）的腹膜壁中发育良好，并显示出与VEGF-C和VEGF-D的mRNA水平升高相关的增强的淋巴管生成。与野生型小鼠相比，植入物的大小和淋巴管生成减少，当从缺乏VEGFR1酪氨酸激酶（TK）结构域的小鼠子宫内膜碎片（TK ^{- / -} ）移植入宿主TK ^{- / -}小鼠（TK ^{- / -} →TK ^{- /-}）。用VEGFR3激酶抑制剂治疗WT→WT小鼠抑制了植入物的大小和淋巴管生成。免疫荧光分析表明，VEGF-C和VEGF-D在CD11b ⁺和S100A4 ⁺细胞中均表达。TK ^-/- →TK ^-/-小鼠的CD11b ⁺和S100A4 ⁺数量较少细胞比WT→WT小鼠。当用胎盘生长因子（PlGF）（一种VEGFR1的特异性激动剂）刺激离体的骨髓（BM）巨噬细胞或培养鼠成纤维细胞时，VEGF-C和VEGF-D的水平以VEGFR1依赖性方式增加。这些结果表明巨噬细胞和成纤维细胞中的VEGFR1信号传导有助于子宫内膜植入物的生长和淋巴管生成。