HIF-1α regulates angiogenesis via Notch1/STAT3/ETBR pathway in trophoblastic cells
HIF-1α regulates angiogenesis via Notch1/STAT3/ETBR pathway in trophoblastic cells
复制标题
HIF-1 α 通过 Notch1/STAT3/ETBR 通路调节滋养层细胞中的血管生成
DOI：
10.1080/15384101.2019.1689481
复制
发表时间：
2019-11-16
期刊：
影响因子：
4.3
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Yu, Nan;Wu, Jian-Li;Li, Wei
背景：子痫前期是一种妊娠相关并发症，是导致母儿死亡的主要原因。尽管广泛的研究，这种疾病的发病机制仍然是未知的。在这里，我们探讨了HIF-1 α和Notch 1/ETBR在先兆子痫中的作用。方法：采用免疫组化、RT-qPCR和western blot方法检测子痫前期患者胎盘组织中Notch 1和ETBR的表达。采用Transwell侵袭实验和体外Matrigel实验检测Notch 1、HIF-1 α和ETBR在滋养层细胞侵袭和血管生成中的作用。此外，我们使用子宫灌注压降低（RUPP）大鼠模型在体内研究先兆子痫。结果：Notch 1和ETBR在子痫前期患者胎盘组织中表达下调。缺氧促进滋养层细胞的侵袭和血管生成，并上调HIF-1 α、Notch 1/ETBR的表达。Notch 1的过表达促进滋养层细胞的侵袭和血管生成，而HIF-1 α抑制剂抑制。Notch 1和ETBR均能促进RUPP大鼠滋养层细胞血管生成。结论：HIF-1 α和Notch 1/ETBR在子痫前期发病中起重要作用。缺氧诱导的HIF-1 α调节Notch 1/ETBR信号，从而调节滋养层细胞的侵袭和血管生成。这些结果揭示了子痫前期的分子机制，并为子痫前期的治疗提供了潜在的靶点。
Background: Preeclampsia is a pregnancy-related complication and the major cause to maternal and fetal mortality. Despite extensive studies, the pathogenesis of this disease still remains unknown. Here we explored the roles of HIF-1 alpha and Notch1/ETBR in preeclampsia. Methods: Immunohistochemistry, RT-qPCR and western blot were used to measure levels of Notch1 and ETBR in placentas of preeclampsia patients. Transwell invasion assay and in vitro Matrigel assay were used to test the functions of Notch1, HIF-1 alpha and ETBR in invasion and angiogenesis of trophoblast cells. In addition, we used reduced uterine perfusion pressure (RUPP) rat model to study preeclampsia in vivo. Results: We found that Notch1 and ETBR were down-regulated in the placenta of patients with preeclampsia. Hypoxia promoted invasion and angiogenesis of trophoblast cells, and up-regulated expressions of HIF-1 alpha, Notch1/ETBR. Overexpression of Notch1 facilitated invasion and angiogenesis of trophoblast cells while HIF-1 alpha inhibitor suppressed. Furthermore, Notch1 or ETBR could promote angiogenesis of trophoblast cells in RUPP rats. Conclusions: Our study reveals that HIF-1 alpha and Notch1/ETBR play important roles in preeclampsia. Hypoxia-induced HIF-1 alpha regulated Notch1/ETBR signaling, thereby modulating invasion and angiogenesis of trophoblast cells. These results shed light on molecular mechanisms of preeclampsia and provide potential targets for preeclampsia therapy.