Hyperinsulinemia restrains endometrial angiogenesis during decidualization in early pregnancy
Hyperinsulinemia restrains endometrial angiogenesis during decidualization in early pregnancy
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DOI：
10.1530/joe-19-0127
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发表时间：
2019-11-01
影响因子：
4
通讯作者：
Gao, Rufei
中科院分区：
文献类型：
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作者：
Chen, Wenqi;Lu, Siyu;Gao, Rufei
先前对胰岛素作用的研究主要集中在新陈代谢上。本研究调查了胰岛素对子宫内膜蜕膜化中血管生成的影响。通过皮下注射胰岛素构建高胰岛素治疗小鼠模型。采用ELISA法检测孕鼠静脉血糖、血清胰岛素、P4、E2、FSH、LH水平。在妊娠小鼠模型和人工诱导蜕膜化小鼠模型的蜕膜化过程中检测蜕膜标志物、血管生成因子和蜕膜血管网络。在高胰岛素处理的 HUVECS 细胞中也检测到管形成能力和血管生成因子表达。为了确认自噬是否参与高胰岛素血症受损的蜕膜血管生成，在体内和体外检测了自噬。蜕膜化过程中，在高胰岛素状态下，血清胰岛素和血糖显着升高，同时卵巢类固醇激素也发生紊乱（P < 0.05），蜕膜标志物BMP2和PRL显着降低（P < 0.05）。子宫CD34染色显示血管窦的大小明显小于对照。体内外高胰岛素治疗后子宫内膜VEGFA表达均显着降低（P < 0.05），而ANG-1和TIE2表达显着升高（P < 0.05）。此外，自噬标志物的异常表达表明自噬参与了蜕膜化过程中的子宫内膜血管生成（P < 0.05）。 HUVEC经自噬抑制剂3-MA处理后，原本受损的细胞管形成能力和VEGFA表达得到修复。这项研究表明，早期妊娠小鼠的高胰岛素血症会损害蜕膜化过程中的子宫内膜血管生成。
Previous research on the role of insulin has focused on metabolism. This study investigated the effect of insulin on angiogenesis in endometrial decidualization. High insulin-treated mouse model was constructed by subcutaneous injection of insulin. Venous blood glucose, serum insulin, P4, E2, FSH and LH levels in the pregnant mice were detected by ELISA. Decidual markers, angiogenesis factors and decidual vascular network were detected during decidualization in the pregnant mouse model and an artificially induced decidualization mouse model. Tube formation ability and angiogenesis factors expression were also detected in high insulin-treated HUVECS cells. To confirm whether autophagy participates in hyperinsulinemia-impaired decidual angiogenesis, autophagy was detected in vivo and in vitro. During decidualization, in the condition of high insulin, serum insulin and blood glucose were significantly higher, while ovarian steroid hormones were also disordered (P < 0.05), decidual markers BMP2 and PRL were significantly lower (P < 0.05). Uterine CD34 staining showed that the size of the vascular sinus was significantly smaller than that in control. Endometrial VEGFA was significantly decreased after treatment with high insulin in vivo and in vitro (P < 0.05), whereas ANG-1 and TIE2 expression was significantly increased (P < 0.05). In addition, aberrant expression of autophagy markers revealed that autophagy participates in endometrial angiogenesis during decidualization (P < 0.05). After treatment with the autophagy inhibitor 3-MA in HUVEC, the originally damaged cell tube formation ability and VEGFA expression were repaired. This study suggests that endometrial angiogenesis during decidualization was impaired by hyperinsulinemia in early pregnant mice.