Upregulation Of CD81 In Preeclampsia:New Insight Into Molecular Mechanisms For This Disease

Preeclampsia(PE)is considered to be initiated by abnormal placentation in the early pregnancy and displays maternal systemic pathophysiological changes in the second or third trimester.Human placental cytotrophoblasts(CTBs)invade the maternal uterine wall and spiral arteries during pregnancy,resulting in the modification of uterine vessels.Inadequate CTB invasion is a key factor involved in the pathological changes that occur during placentation in PE development.Increasing evidence indicates that abnormal CTB invasion is associated with various changes in multiple molecules.CD81,a member of the tetraspanin superfamily,plays significant roles in cell growth,adhesion and motility.In addition,increasing reports indicate that CD81 is one main component of exosome and can be released into the serum or delivered to certain organ and tissure.However,the role of CD81 in human placentation and pregnancy complications remains unknown.In the present study,we investigated the effects of CD81 on human placentation,PE pathogenesis and the molecular mechanisms involved in these events.CD81 expression was sequentially downregulated with gestational advance in CTBs of human placenta.CD81 was expressed on CTB progenitors and preferentially expressed on undifferentiated CTBs from first,second and third trimester control placentas.In contrast,increased CD81 expression was found in extravillous CTBs and syncytiotrophoblasts(STBs)in placentas from patients with early-onset severe PE(sPE).Clinically,increased level of CD81 was detected in sera collected from patients with sPE at the time of disease.Furthmore,separating the serum exosomes and exosome-free samples from sera of patients with sPE and gestational age-matched controls by using differential gravities,we found that upregulated CD81 levels were detected in both the exosome and the exosome-free samples from sPE,and more dramatic differences were observed on exosome-free samples.Overexpressing CD81 in CTBs from human first trimester villi significantly decreased CTB invasion and interruptted endothelial cell functions in vitro.On the molecular level,we characterized a new molecular function of CD81,in which CD81 repressed Akt activation by altering the expression of PDK1 in human trophoblast cells.More importantly,all of the changes in human PE were mimicked in the CD81-induced rat model,including elevation in systolic blood pressure(SBP,113.5±1.95 mmHg v.s.108.76±4.62 mmHg,p<0.01),increased urinary protein concentration(2.52±0.17 v.s.2.20±0.18,Log value,p<0.05)and lower diameters of uterine arteries(71.53±6.39 v.s.105.05±13.40 μm,p<0.01).On the other hand,SBP and urinary protein concentration were observed to be no obvious changes in the Ad-CD81-infected nopregnant rat.Collectively,upregulated CD81 expression are identified in the placenta trophoblasts and sera of the patients with sPE.In vitro,overexpression of CD81 inhibits trophoblast invasion and interrupts endothelial cell functions by repressing the PI3K/Akt signaling pathway.In vivo,overproduction of CD81 in rats triggers PE-like phototypes.