Slit2/Robo4 Signaling: Potential Role of a VEGF-Antagonist Pathway to Regulate Luteal Permeability
Slit2/Robo4 Signaling: Potential Role of a VEGF-Antagonist Pathway to Regulate Luteal Permeability
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DOI：
10.1055/s-0042-113461
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发表时间：
2017-01-01
影响因子：
2.7
通讯作者：
Wulff, C.
中科院分区：
文献类型：
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作者：
Bekes, I.;Haunerdinger, V.;Wulff, C.
黄体（CL）依赖于黄体血管的通透性，而黄体血管的通透性是由人绒毛膜促性腺激素（hCG）通过血管内皮生长因子（VEGF）控制的。在这项研究中，我们研究了潜在的VEGF拮抗剂途径- Slit2/Robo4 -的作用及其对内皮细胞粘附的影响。材料和方法在没有或存在VEGF抑制剂的情况下，用hCG刺激黄体素化颗粒细胞（lgc）。检测VEGF和Slit2的表达。用Slit2或VEGF刺激人脐静脉内皮细胞（HUVECs），检测cadherin 5 （CDH5）和claudin 5 （CLDN5）的基因表达。Robo4敲除后，检测CDH5、CLDN5和内皮通透性。结果hCG刺激人LGCs后，VEGF显著升高，Slit2表达明显抑制。hCG刺激后抑制VEGF的作用不改变Slit2的抑制。Slit2敲低不影响VEGF表达。VEGF刺激HUVECs可显著抑制CDH5和CLDN5基因表达，而Slit2刺激HUVECs可显著增加CDH5和CLDN5基因表达。Robo4敲低，导致CDH5和CLDN5下调，导致通透性显著增加。结论我们的研究结果表明，在CL中存在vegf拮抗剂通路，降低血管通透性。在CL的功能寿命期间，该途径受到hCG的抑制。刺激这一途径可能用于治疗卵巢过度刺激综合征。
Introduction The corpus luteum (CL) is dependent on luteal vascular permeability, which is controlled by human chorionic gonadotropin (hCG) via vascular endothelial growth factor (VEGF). In this study we investigated the role of a potential VEGF antagonist pathway - Slit2/Robo4 - and its influence on endothelial cell adhesion.Materials and Methods Luteinized granulosa cells (LGCs) were stimulated with hCG in the absence or presence of a VEGF inhibitor. The expression of VEGF and Slit2 were measured. Human umbilical vein endothelial cells (HUVECs) were stimulated with Slit2 or VEGF, and gene expressions of cadherin 5 (CDH5) and claudin 5 (CLDN5) were measured. Following Robo4 knockdown, CDH5, CLDN5 and endothelial permeability were measured.Results Stimulation of human LGCs with hCG significantly increased VEGF while Slit2 expression was significantly suppressed. Inhibition of VEGF action after hCG stimulation did not change Slit2 suppression. Slit2 knockdown did not affect VEGF expression. While VEGF stimulation of HUVECs significantly suppressed CDH5 and CLDN5 gene expression, stimulation of HUVECs with Slit2 resulted in a significant increase in CDH5 and CLDN5. Robo4 knockdown was done, leading to downregulation of CDH5 and CLDN5 which resulted in significantly increased permeability.Conclusions Our results indicate the existence of a VEGF-antagonist pathway in the CL that decreases vascular permeability. During the functional life of the CL the pathway is suppressed by hCG. It is possible that stimulation of this pathway could be used to treat ovarian hyperstimulation syndrome.