Netrin-1 通过Notch信号通路调控早发型胎儿生长受限胎盘血管发育的机制研究

In our preliminary studies, we found placental angiodysplasia in smaller fetuses than in larger fetuses in discordant monozygotic twins，and the expression of Netrin-1,a secreted protein that induces targeting vscular growth, decreased significantly in the placenta of smaller fetuses. However, the molecular mechanism how Netrin-1works on placental angiodysplasia is still unknown. We further observed Netrin-1 expression increased under proper concentration of low molecular weight heparin (LMWH), and proliferation and migration ability of human placental MECs enhanced, apoptosis decreased while Netrin-1 increased. Notch signaling pathway is reported to be crucial in biological functions of vascular endothelial cells (VECs)and angiogenesis. Based on these results, we will elucidate Netrin-1 affects biological functions of VECs through Notch signaling pathway, which plays an important role in placental angiodysplasia of early-onset FGR. The purpose of this project is to investigate the mechanism of Notch signaling pathway regulated by Netrin-1 in placental angiogenesis with early-onset fetal growth restriction, and to provide a new insight for the pathogenesis and treatment of early-onset FGR.

我们前期发表论文提示在单合子双胎之一胎儿生长受限中，体重正常胎儿的胎盘血管丰富，而生长受限胎儿的胎盘血管网稀疏、发育不良，调控血管靶向性生长的Netrin-1表达显著降低。然而Netrin-1的表达异常与血管发育不良的关系及具体作用机制仍亟待解决。我们的预实验结果显示特定浓度的肝素可促进Netrin-1的表达，而提高Netrin-1表达可显著增强血管内皮细胞的增殖与迁移能力，并降低细胞凋亡。此外，文献提示Notch通路对血管内皮细胞各项生物学功能及血管发育至关重要。在此基础上，我们提出科学假设：Netrin-1可能通过Notch通路调控胎盘血管内皮细胞各项生物学功能，在胎儿生长受限中发挥重要作用。本研究拟探讨Netrin-1通过Notch信号通路在调控早发型FGR胎盘血管发育的机制，研究结果将加深对胎盘发育调控的认识，为早发型FGR靶向基因治疗提供理论依据，具有重要科学价值及临床意义。

我们前期发表论文提示在单合子双胎之一胎儿生长受限中，体重正常胎儿的胎盘血管丰富 ，而生长受限胎儿的胎盘血管网稀疏、发育不良，调控血管靶向性生长的Netrin-1表达显著降低。通过胎盘血管梯度造影及三维重建发现sIUGR的深部盘血管发育及分布不同于正常双胎。通过截断面积流量计算，sIUGR组胎盘动-静脉吻合的流量显著大于正常对照组，且血液分流的方向是从小胎流向大胎。从胎盘血管发育构造解释了胎盘的血流动力学，是支持我们前期研究中推测sIUGR中双胎血液流向是源于胎盘深部血管吻合的压力差的直接证据，对阐明胎盘血管发育和胎盘血流动力学在FGR发生机制有重要提示作用。我们的实验结果显示发现FGR胎盘上Netri-1、NOTCH-1、Jagged-1、DLL-4及下游通路VEFG表达显著下降。特定浓度的低分子肝素可促进滋养细胞Netrin-1及NOTCH通路表达，出现微血管上皮标志物，提示低分子肝素可能有诱导滋养细胞向微血管内皮转化或血管拟态的作用，支持Netrin-1可能通过Notch通路调控胎盘血管内皮细胞各项生物学功能，在胎儿生长受限中发挥重要作用。研究结果将加深对胎盘发育调控的认识，超声监测胎盘血流为早期预测FGR提供依据，低分子肝素对滋养细胞分化的影响为早发型FGR治疗提供了新的靶点和理论依据，具有重要科学价值及临床意义。