Lymphangiogenesis induced by vascular endothelial growth factor receptor 1 signaling contributes to the progression of endometriosis in mice
Lymphangiogenesis induced by vascular endothelial growth factor receptor 1 signaling contributes to the progression of endometriosis in mice
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DOI：
10.1016/j.jphs.2020.05.003
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发表时间：
2020-08-01
影响因子：
3.5
通讯作者：
Majima, Masataka
中科院分区：
文献类型：
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作者：
Hattori, Kyoko;Ito, Yoshiya;Majima, Masataka
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) 信号传导是否在子宫内膜异位症期间的淋巴管生成中发挥作用。来自野生型 (WT) 小鼠的子宫内膜碎片移植到宿主 WT 小鼠的腹膜壁 (WT -> WT) 发育良好，并表现出与 VEGF-C 和 VEGF-D mRNA 水平增加相关的淋巴管生成增强。与WT小鼠相比，当将缺乏VEGFR1酪氨酸激酶（TK）结构域（TK-/-）的小鼠子宫内膜片段移植到宿主TK-/-小鼠（TK-/--> TK-/-）中时，植入物尺寸和淋巴管生成减少。用 VEGFR3 激酶抑制剂治疗 WT -> WT 小鼠可抑制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(+) 细胞数量低于 WT -> WT 小鼠。当用胎盘生长因子（PlGF）（VEGFR1 的特异性激动剂）刺激分离的骨髓（BM）来源的巨噬细胞或培养的小鼠成纤维细胞时，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。 (C) 2020 作者。由 Elsevier B.V. 代表日本药理学会制作和主办。
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. (C) 2020 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.