Sex differences in renin-angiotensin-aldosterone system affect extracellular volume in healthy subjects

Several studies reported sex differences in aldosterone. It is unknown whether these differences are associated with differences in volume regulation. Therefore we studied both aldoste

Perifere vaatreactiviteit in de gezonde en hypertensieve zwangerschap:een pre-eclampsie diermodel

Introduction Preeclampsia is a pregnancy specific syndrome, clinically characterized by the presence of hypertension associated with proteinuria in the second half of pregnancy. The fetus is often growth restricted due to increased vascular resistance in the placenta which causes decreased blood flow. Preeclampsia complicates about 5% of pregnancies and is a leading cause of maternal and perinatal mortality. The pathophysiology of preeclampsia remains unknown, but seems to be multifactorial. Preeclampsia only occurs in the presence of a placenta. Possible mechanisms implicated in the pathogenesis are: endothelial dysfunction, an inflammatory route, oxidative stress, coagulation activation, and the renin angiotensin system (RAS). Angiotensin II (AngII) is the most important component of the RAS. Binding of AngII on the angiotensin II type I receptor, causes vasoconstriction. This receptor has a higher expression in the placenta of preeclamptic women, compared to the healthy pregnant women. The decreased blood flow seen in the placenta of preeclamptic women could be caused by this increased AngII sensitivity. The vasodilatation route induced by acetylcholine could be impaired through the endothelial dysfunction. It is possible that this mechanism causes the development of hypertension and the impaired blood flow to the placenta. This study addresses two questions: 1. What is the peripheral vessel reactivity to angiotensin II in a preeclamptic rat model and in healthy pregnant rats? 2. How is endothelium dependent vasodilatation regulated in a preeclamptic rat model and in healthy pregnant rats? Materials and Methods Thirty-seven female Wistar rats were divided into four groups. Two pregnant and two non-pregnant groups, divided in saline infusion and endotoxin infusion six days before they were sacrificed. After decapatization, the aorta was isolated and placed in a temperature controlled contraction experimental set up. After incubation with different blockers, acetylcholine and angiotensin II concentration response curves were made. Results The aorta of pregnant rats shows a significant increased AngII mediated vasoconstriction respectively AngII mediated vasodilatation compared to healthy pregnant rats (p=0,046; p=0,037) and compared to the preeclamptic rat (p=0,022; p=0,048). No difference is found in AngII mediated vasoconstriction respectively AngII mediated vasodilatation between the preeclamptic rat compared to the healthy non-pregnant rat (p=0,791; p=0,862) Vasocontractile prostaglandin is less present in healthy pregnant rats, compared to preeclamptic rats. Endothelial derived hyperpolarization factor might not play a role in the acetylcholine mediated vasodilatation in the aorta of a pregnant rat, but it might play a role in the aorta of a non-pregnant rat. Conclusion Preeclamptic rats physiological behave like the non-pregnant rats. Possibly, preeclampsia reverses the adjustments of the body to pregnancy.

From preeclampsia to renal disease: Mechanistic studies

Vrouwen die preeclampsie hebben doorgemaakt zijn kwetsbaar voor het ontwikkelen van hart-, vaat, en nierziekten. Of dit komt door preeclampsie zelf of door gemeenschappelijke risicofactoren voor preeclampsie en nierziekten, is onbekend. Bovendien zijn de mechanismen die ten grondslag liggen aan dit verhoogde risico onbekend. Onze hypothese is dat verhoogde angiotensine II (ang II) gevoeligheid en endotheel dysfunctie betrokken zijn. Hiervoor hebben we eerst een preeclampsie ratmodel gevalideerd voor deze kenmerken. Vervolgens hebben we postpartum studies uitgevoerd in vrouwen en in ratten na (experimentele) preeclampsie. Ons doel was om te onderzoeken of de afwijkingen die gezien worden tijdens preeclampsie (veranderde renale hemodynamiek, toegenomen ang II gevoeligheid en endotheel dysfunctie), postpartum persisteerden om zo te onderzoeken of deze mechanismen betrokken zijn bij het verhoogde risico op nierziekten. Het ophelderen van deze mechanismen helpt mee te ontdekken waarom vrouwen na preeclampsie meer gevoelig zijn voor het ontwikkelen van nierziekten en is tevens een belangrijke stap richting het ontwikkelen van follow-up en preventieve behandeling. Onze studies in vrouwen en ratten na (experimentele) preeclampsie laat langetermijngevolgen zien van preeclampsie. Onze studies wijzen in de richting dat preeclampsie zelf een rol speelt in de postpartum verstoringen en hiermee deze vrouwen kwetsbaar maakt voor het ontwikkelen van nierziekten op de lange termijn. Wij tonen aan dat postpartum renale hemodynamiek, persisterende ang II gevoeligheid, endotheeldysfunctie en vaatstijfheid, allen mogelijkheden bieden voor verder onderzoek naar de exacte mechanismen achter het verhoogde risico op nierziekten. Een voorgeschiedenis van preeclampsie identificeert jonge vrouwen die een verhoogd risico hebben op het ontwikkelen hart-, vaat- en nierziekten. Dit geeft vele mogelijkheden voor preventieve behandeling in deze specifieke groep jonge vrouwen, zelfs in de afwezigheid van bekende cardiovasculaire risicofactoren

From preeclampsia to renal disease: a role of angiogenic factors and the renin-angiotensin aldosterone system?

Complicating up to 8% of pregnancies, preeclampsia is the most common glomerular disease worldwide and remains a leading cause of infant and maternal morbidity and mortality. Although the exact pathogenesis of this syndrome of hypertension and proteinuria is still incomplete, a consistent line of evidence has identified an imbalance of proangiogenic and anti-angiogenic proteins as a key factor in the development of preeclampsia. Furthermore, more attention has been recently addressed to the renin-angiotensin aldosterone system (RAAS), to provide understanding on the hypertension of preeclampsia. The imbalance of the RAAS and the imbalance between angiogenic and anti-angiogenic factors, which may be both common to preeclampsia and chronic kidney disease (CKD), might explain why a history of preeclampsia predisposes women to develop CKD. In this review, we briefly describe the characteristics of preeclampsia with a focus on the mechanisms of angiogenesis and the RAAS and its role in the pathogenesis of preeclampsia. Our main focus will be on the intriguing association between preeclampsia and the subsequent increased risk of developing CKD and on the potential mechanisms by which the risk of CKD is elevated in women with a history of preeclampsia

High sFlt-1 Concentrations During Pregnancy Modulate the Ppara Promoter Methylation in the Fetal Liver

Background An adverse prenatal environment significantly increases the risk of chronic metabolic diseases in the offspring. The mechanisms underlying such programming are unclear but may involve epigenetic modifications that lead to altered fetal gene expression. It was demonstrated that poor maternal nutrition affects the DNA methylation status of important transcriptional factors in the liver. However, little attention has been given to other pathological events during pregnancy e.g. increased concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1). Our working hypothesis is that increased sFlt-1 concentrations in the mother can influence the developmental plasticity and the phenotype of the offspring via resetting of DNA methylation marks. Methods Pregnant Sprague-Dawley rats were injected with control or adenovirus overexpressing sFlt-1 on gestational day (GD 8). Fetal plasma, body and organ weight were assessed on GD 19. Microarray analysis was performed to assess the offspring liver gene expressions. The candidate gene methylation status was verified by pyrosequencing. Results Plasma concentrations of sFlt-1 peaked 48 h post injections in the treated animals, and the high concentrations were maintained until the end of the pregnancy. The fetal sFLt-1 concentrations were increased and body weight and length were decreased in the sFlt-1 group. There were no significant differences in the brain weight between the groups, but the livers were smaller in comparison to the respective control group. Microarray analysis revealed 623 differentially expressed genes in the fetal liver. The functional analysis indicated a significant effect on lipid metabolism and in particular fatty acid beta-oxidation. Moreover, Ppara, a transcriptional factor and key regulator of hepatic lipid metabolism, was one of the most induced genes by the high sFlt-1 concentrations present in the mother and in the offspring. In addition, we performed pyrosequencing, to confirm whether Ppara overexpression is accompanied by changes in the methylation of the respective promoter. The promoter region of Ppara revealed decreased methylation in the high sFlt-1 group in comparison to the controls, which is in accordance to the observed gene overexpression. Conclusion Our data show that increased sFlt-1 concentrations in the mother and the offspring lead to growth restriction, brain sparing and Ppara upregulation in the liver. This is accompanied by Ppara promoter hypomethylation. Overall this suggests that epigenetic mechanism may induce the altered phenotype of the offspring via high sFlt-1 maternal concentrations. Support or Funding Information This work was supported by the Netherlands Organization for Health Research and Development (ZonMW, grant number 91211053)