The Mechanism Of Vascular Dysfunction On Offspring Of Hypertension In Pregnancy

1 Differential heat shock protein expression of vessels from hypertension in pregnancy offspringObjective:Hypertension in pregnancy(HIP)occurs in approximately 10%pregnant women.It's still one of the most common reasons of perinatal mother and fetus mortality and morbidity.However,the concern on its short-term clinical features let us ignored the long-term effect it may have towards the offspring.Recently,there are several epidemiology studies show that the adult offspring of HIP could have dysfunctions on cardiovascular system,yet we have poorly understood for its underlying mechanism.Heat shock protein(HSP)is a group of functional proteins that have important physical roles in human body,include the protection effect on other signaling pathways during stress.Therefore,we present this study to analysis whether the protein expression pattern would change in umbilical artery of HIP offspring and especially the changes of HSPs.Materials and methods:After informed consents,we collected umbilical cord tissue from normal and HIP women underwent cesarean delivery.Separate and extract protein from umbilical artery from both group,with sample preparation,use iTRAQ-2D-LC-MS/MS quantitative protcomic technology to identify proteins and then proceed bioinformatics analysis.Test HSPs expression in mRNA and protein level.Results:We identified 1496 different proteins with quantitative information,46 of them have significant difference between two group(22 up-regulated,24 down-regulated).After bioinformatics analysis we found a group of HSPs that have altered expression,include HSP27,HSP60,HSP70 and HSP90,among them,HSP60 has a dramatically down-regulated in HIP group.Conclusion:In this study we confirmed that the alternative intrauterine environment of HIP can led to altered protein expression pattern in umbilical artery.The differential proteins were highly related to cardiovascular system development.This result reminds us that the offspring of PIH may have dysfunction on cardiovascular development,with further increasing risk of vessel based diseases.This research also revealed several important HSPs were altered in this process and provide new thoughts on mechanism researches.2 Observation of adult offspring vascular function of hypertension in pregnancy use a rat modelObjective:Recently,fetal-origins adult disease has attracted more and more concern.Researchers found that altered intrauterine environment can led to multiple risks of disease increasing in adult life.Hypertension in pregnancy(HIP)is one of the most severe pregnant complications.Epidemiological studies show that the adult offspring of HIP have an elevated risk on cardiovascular and cerebrovascular diseases.However,the underlying mechanism remains unclear.In this study,we use animal model to investigate the impact of HIP on vascular function of adult offspring.Materials and methods:Use L-NAME to cause evaluated blood pressure(BP)on Sprague-Dawley pregnant rats from Day 13 until delivery(mimic the clinical feature of human HIP).Monitoring BP and body weight(BW)of offspring continuously.Separate mesenteric artery at offspring age 6m and ly,use small vessel wire myography to test the contraction and relaxation ability of these arteries,respectively.Use HE staining to observe morphology change in both groups.Results:We successfully built the HIP animal model.The BW of offspring born from HIP mothers were slightly lower than offspring born from normal mothers at birth,but become identical after 3w.The systolic BP began to increase in HIP offspring from 8w,and the diastolic BP also began to rise from 6m compared to the normal offspring.Wire myography shows that the small mesenteric artery of HIP offspring has higher sensitivity to vessel angiotonics at 6m,and has less sensitivity to vasodilators at 1y compared to the control group.In the mean time we also can observe mesenteric small artery morphology change in HIP offspring.Conclusion:This study revealed that the adult offspring of HIP has a higher risk on hypertension and vascular dysfunction.As small artery structure altered,with ageing,both contraction and relaxation ability of small artery impaired one after another in HIP offspring.Depends on these findings,we can provide that offspring born from HIP has a long term risk of cardiovascular diseases in adult life.Further mechanism investigation is needed.3 Alternative splicing variant of mineralocorticoid receptor in preeclampsia umbilical artery and placenta and its impact on offspring endothelial cell dysfunctionObjective:Preeclampsia(PE)is one of the most severe pregnant complications.The occurrence of PE appeared in family aggregation.Epidemiology researches pointed that offspring born from PE has a higher risk in cardiovascular diseases than normal offspring.There are several hypotheses in PE etiology.Mineralocorticoid receptor(MR)is an important receptor which mediate aldosterone physiology effects.In clinical experience,PE patients often shows a aldosterone relatively low features.This study is to investigate the implications of MR and its alternative splicing variant(ASV)in PE etiology and offspring endothelial cell functions.Materials and methods:After informed consents,collect umbilical artery and placenta tissue from normal and PE offspring underlying cesarean.Observe the moiphology changes in each group.Test MR and its ASV expression.Built overexpression system of MR and MR ASV in epithelial cells and exam the biology features and downstream gene expression.Use stable overexpressed primary endothelial cells to test the impact of MR ASV on endothelial cell functions.Results:With HE staining,we observed that the vessels from PE group has a narrower lumen and loose structure on vascular wall compared with control group.Wild type MR(MR-WT)was detected in both groups,MR-WT expression in PE group is lower than control group in both tissues.A MR ASV was also found in PE group,which is lack of Exon 5(MR-D5),is highly expressed.In the overexpression system use 293FT cells,we found that MR-D5 lost nuclear shuttling ability,and caused multiple MR downstream genes expression altered related to membrane ion and water exchange.In MR stable overexpression endothelial cells,the proliferation ability,migration ability and angiogenesis ability in MR-D5 group are all damaged.Conclusion:The abnonnal expression of MR-D5 in PE placenta and umbilical artery would affects the cell generation and impairs the function of endothelial cells,furthermore,aggravate the pathological conditions of PE,lead to vascular dysfunction in offspring.On the other hand,MR-D5 affects the ion channel expression in endothelial cells,which alters the ion and water exchange on the vessel lumen.This study provided us a new way to understand PE etiology and the mechanism of increasing risk of cardiovascular diseases of PE offspring...