卡博替尼对子宫内膜异位症小鼠异位内膜中血管内皮细胞生长因子受体2的作用机制研究

Mechanism of cabotinib on vascular endothelial growth factor receptor 2 in ectopic endometrium of endometriosis mice

目的研究卡博替尼对子宫内膜异位症模型小鼠血管生成的作用机制。方法通过手术移植小鼠子宫内膜组织块到肠系膜处的方法,建立子宫内膜异位症模型小鼠。将造模成功的模型小鼠随机分为3组:模型组和低、高剂量实验组,每组13只。低、高剂量实验组小鼠分别每天灌胃10和20μg·g;卡博替尼,模型组小鼠每天灌胃等体积灭菌生理盐水,连续28 d。计算每个子宫内膜植入组织的表面积;荧光定量反转录聚合酶链式反应和蛋白质印迹法分别检测血管内皮生长因子受体2(VEGFR2)信号通路相关基因和蛋白表达水平。结果模型组和低、高剂量实验组的病变面积分别为(64.00±3.58),(48.00±2.39)和(20.00±1.25)mm^(2);这3组的p-VEGFR2/VEGFR2表达水平分别为(100.00±0.00)%,(62.27±3.45)%和(40.32±2.08)%;这3组的p-细胞外调节蛋白激酶/细胞外调节蛋白激酶(p-ERK/ERK)表达水平分别为(100.00±0.00)%,(51.34±2.68)%和(28.26±1.29)%;这3组的p-c-Jun氨基末端激酶/c-Jun氨基末端激酶(p-JNK/JNK)表达水平分别为(100.00±0.00)%,(64.51±2.79)%和(31.83±1.36)%;这3组的p-丝裂原活化蛋白激酶/丝裂原活化蛋白激酶(p-p38/p38)表达水平分别为(100.00±0.00)%,(52.49±2.58)%和(34.03±1.25)%,低、高剂量组与模型组相比,差异均有统计学意义(均P<0.05)。结论卡博替尼通过抑制VEGFR2信号通路发挥抗血管生成作用,显着抑制实验性子宫内膜异位症的发展。

Objective To study the mechanism of cabozantinib on angiogenesis in mice with endometriosis.Methods Endometriosis model mice were established by surgical transplantation of endometrial tissue into the mesentery.The model mice that were successfully modeled were randomly divided into three groups:the model group,the low and high experimental groups,with 13 mice in each group.The mice in the two experimental groups of low and high doses were gavaged intraperitoneally with 10 and 20μg·g^(-1) cabozantinib each day,mice in the model group were gavaged intraperitoneally with an equal volume of sterile normal saline every day for 28 d.Calculate the surface area of each endometrial implanted tissue.Fluorescence quantitative polymerase chain reaction and Western blot were used to detect the expression levels of vascular endothelial growth factor(VEGF)signaling pathway related genes and proteins.Results The lesion area of the model group and the low and high dose experimental groups were(64.00±3.58),(48.00±2.39)and(20.00±1.25)mm^(2),respectively;the expression levels of p-VEGFR2/VEGFR2 in these three groups were(100.00±0.00)%,(62.27±3.45)%and(40.32±2.08)%,respectively;the expression levels of p-Protein kinase R-like endoplasmic reticulum kinase/extracellular regulated protein kinase(p-ERK/ERK)in these three groups were(100.00±0.00)%,(51.34±2.68)%and(28.26±1.29)%;the expression levels of p-c-Jun amino terminal kinase/c-Jun amino terminal kinase(p-JNK/JNK)in these three groups were(100.00±0.00)%,(64.51±2.79)%and(31.83±1.36)%,respectively;the expression levels of p-mitogen activated protein kinase/mitogen activated protein kinase(p-38 MAPK/p38 MAPK)in these three groups were(100.00±0.00)%,(52.49±2.58)%and(34.03±1.25)%.The differences between the experimental group and the model group were statistically significant(all P<0.05).Conclusion Cabozantinib exerts an anti-angiogenic effect by inhibiting the VEGFR2 signaling pathway,and significantly inhibits the development of experimental endometriosis.