Vascular endothelial growth factor 165 inhibits pro-fibrotic differentiation of stromal cells via the DLL4/Notch4/smad7 pathway
Vascular endothelial growth factor 165 inhibits pro-fibrotic differentiation of stromal cells via the DLL4/Notch4/smad7 pathway
复制标题
血管内皮生长因子 165 通过 DLL4/Notch4/smad7 途径抑制基质细胞的促纤维化分化
DOI：
10.1038/s41419-019-1928-z
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发表时间：
2019-09-12
影响因子：
9
通讯作者：
Hu, Yali
中科院分区：
文献类型：
--
作者：
Lv, Haining;Nan, Ziqing;Hu, Yali
子宫内膜纤维化是阿舍曼综合征（AS）的主要病理特征，是导致子宫不孕的主要原因。人们对于正常月经周期中子宫内膜的管腔/腺上皮细胞和基质细胞中 VEGF165 的表达了解很多；然而，人们对VEGF165在子宫内膜纤维化中的作用和机制知之甚少。在此，我们报道 VEGF165 是子宫内膜基质细胞中抑制 α-SMA 和胶原蛋白 1 表达的关键调节因子。与人类对照受试者相比，AS 患者子宫内膜中 VEGF165 表达减少，纤维化标志物表达和胶原蛋白生成增加。条件性 VEGF 减少的小鼠和 VEGF165 缺失的子宫内膜基质细胞均显示出纤维化表型。外源性 VEGF165 可以抑制人原代子宫内膜基质细胞中 TGF beta 1 诱导的 α-SMA 和胶原蛋白 1 的表达。然而，当 smad7 或 Notch4 的表达受到抑制或 Notch 信号传导被阻断时，这种有益作用会受到阻碍，这表明 smad7 和 Notch4 是 VEGFA 功能所必需的下游分子。总体而言，我们的结果揭示了 VEGF165 通过诱导 DLL4/Notch4/smad7 抑制基质细胞促纤维化分化的临床靶向策略，这为 AS 治疗铺平了道路。
Endometrial fibrosis is the main pathological feature of Asherman's syndrome (AS), which is the leading cause of uterine infertility. Much is known about the expression of VEGF165 in luminal/glandular epithelial cells and stromal cells of the endometrium in normal menstrual cycles; however, less is known about the role and mechanism of VEGF165 in endometrial fibrosis. Herein, we report that VEGF165 is a key regulator in endometrial stromal cells to inhibit alpha-SMA and collagen 1 expression. Compared to human control subjects, patients with AS exhibited decreased VEGF165 expression in the endometrium along with increased fibrotic marker expression and collagen production. A fibrotic phenotype was shown in both mice with conditional VEGF reduction and VEGF165-deleted endometrial stromal cells. Exogenous VEGF165 could suppress TGF beta 1-induced alpha-SMA and collagen 1 expression in human primary endometrial stromal cells. However, this beneficial effect was hindered when the expression of smad7 or Notch4 was inhibited or when Notch signaling was blocked, suggesting that smad7 and Notch4 are essential downstream molecules for VEGFA functioning. Overall, our results uncover a clinical targeting strategy for VEGF165 to inhibit pro-fibrotic differentiation of stromal cells by inducing DLL4/Notch4/smad7, which paves the way for AS treatment.