Expression Change And Mechanism Of ELABELA/APLNR In The Pathogenesis Of Preeclampsia

Background and objectives:Trophoblast invasion disorder and abnormal vascular remodeling are important characteristics in the pathogenesis of preeclampsia.However,the etiology and pathogenesis of preeclampsia are still unknown.ELABELA?ELA?is a recently discovered small molecule peptide hormone related to angiogenesis,also known as APELA,TODDLER,ENDE,and its receptor is APLNR.During embryogenesis,ELABELA/APLNR plays a vital role in the formation of three germ layers and fetal heart development.It is expressed in the cytotrophoblast cells and syncytiotrophoblast cells of placental tissue during early pregnancy,and has the ability to regulate the invasion of trophoblast effect.Existed studies have shown that pregnant mice with Elabela gene knockout have preeclampsia?PE?symptoms such as hypertension and proteinuria.However,expression change and mechanism of ELABELA/APLNR are not very clear in the pathogenesis of preeclampsia.Therefore,this project intends to detect the change of expression level of ELABELA/APLNR in preeclampsia placenta and further explore its role in the preeclampsia.Methods:1.The expression levels of ELABELA/APLNR in normal and preeclamptic placenta were detected by immunohistochemical method.2.By injecting lipopolysaccharide?LPS?into the tail vein of rats,animal models of preeclampsia?LPS group?were established.3.By subcutaneously implanting an osmotic administration pump,the rats were divided into normal saline group?NS group?,lipopolysaccharide group?LPS group?,and ELA+LPS group.The study aimed to observe the effect of ELABELA on arterial blood pressure,urine protein,fetal and placental weight,placental tissue structure,placental angiogenesis,genes related to placental development,angiotensin ??Ang ??in peripheral blood,and thromboxane B₂?TXB₂?and 6-ketoprostaglandin F_1?(6-keto PGF_1?)levels in preeclampsia rats.Results:1.It was found that ELABELA was mainly expressed in syncytiotrophoblast cells of placental tissue by immunohistochemical method during normal pregnancy.Compared with the normal pregnancy group,its expression level was significantly decreased in placental tissue of preeclampsia patients;APLNR was also expressed in syncytiotrophoblast cells of the villi,compared with the normal pregnancy group,its expression level in placenta tissue in preeclampsia did not change significantly.2.In GD15 and GD16,compared with the NS group,the systolic blood pressure of the rats in the LPS group was significantly increased?P<0.001?,and the urine protein content was significantly increased?P<0.01?.In addition,compared with the NS group,the trophoblast giant cells in the junctional area of placentas were significantly reduced,and angiogenesis in the labyrinth area,was poorly formed,and villous necrosis significantly increased in the LPS group;the expression level of ELABELA in the placenta tissue was significantly reduced,but the expression level of APLNR between the NS group and the LPS group did not change significantly.3.Compared with the LPS group,the systolic blood pressure in the ELA+LPS group was significantly reduced?P<0.01?,the urine protein content was significantly reduced?P<0.001?,and the average fetal weight was significantly increased?P<0.001?,while the average placental weight was no significant change?P>0.05?.4.Compared with the LPS group,the trophoblast giant cells in the junctional area increased and villus necrosis in the labyrinth area decreased,and the total area of the placenta increased significantly?P<0.05?,and the area of the labyrinth area increased significantly in the ELA+LPS group?P<0.05?;However,there was no significant difference in the area of the junctional area and the ratio of the area of the junctional area to the labyrinth area?P>0.05?among three groups.5.Compared with the NS group,the area of Laminin-positive areas in the LPS group was significantly reduced?P<0.001?,and the expression level of placental development gene Fosl1 mRNA was significantly decreased?P<0.001?,and the expression level of Esx1 mRNA was significantly increased?P<0.05?,and the Hand1mRNA expression level was significantly increased?P<0.001?,and the Ascl2 mRNA expression level was significantly increased?P<0.001?.After ELABELA was applied,the area of the Laminin staining area in the ELA+LPS group increased significantly?P<0.001?,and the Fosl1 mRNA expression level was significantly increased?P<0.001?,and the expression level of Esx1 mRNA decreased significantly?P<0.05?,and the expression level of Hand1 mRNA decreased significantly?P<0.05?,but the expression level of Ascl2 mRNA did not change significantly?P>0.05?.6.ELISA analysis showed that there was no significant difference in the levels of peripheral blood angiotensin ? among the NS group,the LPS group,and the ELA+LPS group?P>0.05?.7.Radioimmunoassay showed that compared with the NS group,the urine TXB₂level?P<0.001?,6-keto PGF_1?level?P<0.01?,and TXB₂/6-keto PGF_1?ratio?P<0.001?all were significantly increased.Compared with the LPS group,TXB₂ level?P<0.001?,6-keto PGF_1?level?P<0.01?,and TXB₂/6-keto PGF_1?ratio?P<0.001?in the ELA+LPS group are significantly reduced.Conclusion:1.Compared with normal pregnancy,the expression level of ELABELA in placental tissue of patients with preeclampsia was significantly reduced,while the expression level of APLNR was not significantly changed.2.The application of ELABELA can significantly improve blood pressure,urinary protein,average fetal weight,development of the placenta,and the area of Laminin-positive areas in preeclampsia rats which mechanism may be involved in the TXB2/6-keto PGF1? ratio.