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Several studies have shown that women with a preeclamptic pregnancy exhibit an increased risk of cardiovascular disease. However, the underlying molecular mechanisms are unknown. Animal models are essential to investigate the causes of this increased risk and have the ability to assess possible preventive and therapeutic interventions. Using the latest technologies such as speckle tracking echocardiography (STE), it is feasible to map subclinical changes in cardiac diastolic and systolic function as well as structural changes of the maternal heart. The aim of this work is to compare cardiovascular changes in an established transgenic rat model with preeclampsia-like pregnancies with findings from human preeclamptic pregnancies by STE. The same algorithms were used to evaluate and compare the changes in echoes of human and rodents. Parameters of functionality such as global longitudinal strain (animal &minus, 23.54 &plusmn, 1.82% vs. &minus, 13.79 &plusmn, 0.57%, human &minus, 20.60 &plusmn, 0.47% vs. &minus, 15.45 &plusmn, 1.55%) as well as indications of morphological changes such as relative wall thickness (animal 0.20 &plusmn, 0.01 vs. 0.25 &plusmn, 0.01, human 0.34 &plusmn, 0.01 vs. 0.40 &plusmn, 0.02) are significantly altered in both species after preeclamptic pregnancies. Thus, the described rat model simulates the human situation quite well and is a valuable tool for future investigations regarding cardiovascular changes. STE is a unique technique that can be applied in animal models and humans with a high potential to uncover cardiovascular maladaptation and subtle pathologies.

Intrauterine growth restriction (IUGR) is a condition whereby a fetus is unable to achieve its genetically determined potential size. IUGR is a global health challenge due to high mortality and morbidity amongst affected neonates. It is a multifactorial condition caused by maternal, fetal, placental, and genetic confounders. Babies born of diabetic pregnancies are usually large for gestational age but under certain conditions whereby prolonged uncontrolled hyperglycemia leads to placental dysfunction, the outcome of the pregnancy is an intrauterine growth restricted fetus with clinical features of malnutrition. Placental dysfunction leads to undernutrition and hypoxia, which triggers gene modification in the developing fetus due to fetal adaptation to adverse utero environmental conditions. Thus, in utero gene modification results in future cardiovascular programming in postnatal and adult life. Ongoing research aims to broaden our understanding of the molecular mechanisms and pathological pathways involved in fetal programming due to IUGR. There is a need for the development of effective preventive and therapeutic strategies for the management of growth-restricted infants. Information on the mechanisms involved with in utero epigenetic modification leading to development of cardiovascular disease in adult life will increase our understanding and allow the identification of susceptible individuals as well as the design of targeted prevention strategies. This article aims to systematically review the latest molecular mechanisms involved in the pathogenesis of IUGR in cardiovascular programming. Animal models of IUGR that used nutrient restriction and hypoxia to mimic the clinical conditions in humans of reduced flow of nutrients and oxygen to the fetus will be discussed in terms of cardiac remodeling and epigenetic programming of cardiovascular disease. Experimental evidence of long-term fetal programming due to IUGR will also be included.

CX3CL1, which is a chemokine involved in many aspects of human pregnancy, is a membrane-bound chemokine shed into circulation as a soluble isoform. Placental CX3CL1 is induced by inflammatory cytokines and is upregulated in severe early-onset preeclampsia. In this study, the hypothesis was addressed whether angiotensin II can deregulate placental CX3CL1 expression, and whether CX3CL1 can promote a pro-inflammatory status of monocytes. qPCR analysis of human placenta samples (n = 45) showed stable expression of CX3CL1 and the angiotensin II receptor AGTR1 throughout the first trimester, but did not show a correlation between both or any influence of maternal age, BMI, and gestational age. Angiotensin II incubation of placental explants transiently deregulated CX3CL1 expression, while the angiotensin II receptor antagonist candesartan reversed this effect. Overexpression of recombinant human CX3CL1 in SGHPL-4 trophoblasts increased adhesion of THP-1 monocytes and significantly increased IL8, CCL19, and CCL13 in co-cultures with human primary monocytes. Incubation of primary monocytes with CX3CL1 and subsequent global transcriptome analysis of CD16+ subsets revealed 81 upregulated genes, including clusterin, lipocalin-2, and the leptin receptor. Aldosterone synthase, osteopontin, and cortisone reductase were some of the 66 downregulated genes present. These data suggest that maternal angiotensin II levels influence placental CX3CL1 expression, which, in turn, can affect monocyte to trophoblast adhesion. Release of placental CX3CL1 could promote the pro-inflammatory status of the CD16+ subset of maternal monocytes.

Introduction: Preeclampsia (PE) is associated with an increased cardiovascular risk in later life, especially in women after early-onset PE. We and others have shown that activating antibodies against angiotensin II receptor type 1 (AT1-) are present in women with PE, even after pregnancy. Further, regulatory (auto-) antibodies against G-coupled receptors (GPCR) have been shown to contribute to cardiovascular disease. Hypothesis: Regulatory autoantibodies’ titers are elevated in women with a history of early onset PE and correlate to physiological parameters and clinical outcomes. Methods: Autoantibodies against AT1-, β1- adrenergic receptors, endothelin I receptor A (ETAR), protease-activated receptor 1 (PAR1) and C-X-C3 chemokine binding receptors (CXCR3) were determined by using commercially available ELISA (Celltrend, Luckenwalde, Germany) in women 10 years after after PE pregnancy or control pregnancy. We investigated samples from the PREVFEM cohort (PReeclampsia Risk EValuation in FEMales), a retrospective matched case-control study, which was performed in Zwolle, The Netherlands, from 2008 until 2010. All women registered in the early preeclampsia database as well as an equal number of age-matched females without preeclampsia from the regular obstetric database in the same time period (1991-2007) were invited to participate in the PREVFEM study. Results: Women with history of early PE had higher prevalence of hypertension than controls (42.7% vs 8.3%, p < 0.001). Women with the lowest combined levels of autoantibodies and a history of early PE had significantly higher SBP (mean difference = 11.54 mmHg, 95% CI [4.39; 18.70], p < 0.001), DBP (mean difference = 7.75 mmHg, 95% CI [2.42; 13.08], p < 0.001), and MAP (mean difference = 9.02 mmHg, 95% CI [3.24; 14.79], p < 0.001) compared to the controls. The titer levels of single regulatory AT1-, β1-, ETAR-, PAR1- and CXCR3-autoantibodies were not different between control and former PE women 10 years after index pregnancy. Conclusions: Hypertension is a common problem after preeclamptic pregnancy in middle-aged women. Regulatory autoantibodies are not sufficient alone to cause hypertension or other pathologic conditions, but together with other risk factors such as pathological pregnancy might drive the whole balance towards pathophysiologic conditions. Further studies are needed to investigate the potential of regulatory autoantibodies against GPCR as presymptomatic biomarkers identifying women at particular cardiovascular risk., Advances in RAB Research, Vol 1 No 1 (2018)

Die Schwangerschaftserkrankung Präeklampsie ist eine Multisystemerkrankung und die Hauptursache für mütterliche und kindliche Morbidität und Mortalität. Sie manifestiert sich ab der 20. Schwangerschaftswoche durch Anstieg des Blutdrucks, einhergehend mit einer Proteinurie, hat jedoch ihren Ursprung weit früher. Durch eine abnormale Plazentation kommt es zur Ausbildung eines uteroplazentaren Syndroms, welches sich dann zu einem maternalen Syndrom translatiert. Weltweit sind ca. 5-10 % aller Schwangerschaften betroffen und Mutter wie Kind tragen im weiteren Leben ein erhöhtes Risiko für kardiovaskuläre Erkrankungen. Zurzeit steht keine geeignete Therapie zur Verfügung, die sowohl die Gesundheit des Kindes als auch der Mutter gleichermaßen berücksichtigt. Eine grundlegende Charakterisierung der Ursachen und Mechanismen dieses Syndroms sind deshalb unabdingbar. Zielstellung dieser Arbeit ist es, grundlegende Arbeiten unserer Arbeitsgruppe zu beschreiben und die dargestellten Faktoren und Mechanismen in einen Zusammenhang zustellen. Fokus hierbei soll auf Systeme gelegt werden, die bei Bluthochdruck- und kardiovaskulären Erkrankungen eine wichtige Rolle spielen, wie das Renin- Angiotensin-System (RAS), das Cytochrom P450 (CYP)-System und Adipozytokine. Die hier ausgewählten Originalarbeiten unserer Gruppe beschreiben diese Systeme und deren zugrunde liegenden Mechanismen in der Präeklampsie unter Einbeziehung von geeigneten Methoden wie Charakterisierungen von Patientenmaterial, in vitro- und ex vivo Funktionsstudien sowie Tierstudien. Das transgene Rattenmodell mit präeklampsieähnlichen Phenotyp soll hier ebenfalls näher betrachtet und das Zusammenspiel aus uteroplazentarer Einheit und maternaler Zirkulation eingehender diskutiert werden. Die Originalarbeiten zeigen, dass das RAS in der Pathologie der Präeklampsie beteiligt ist und verdeutlichen ebenfalls die Bedeutung des uteroplazentaren RAS in der normal verlaufenden Schwangerschaft. Zudem geben die Daten Einblicke in das RAS im Kontext des präeklamptischen uteroplazentaren Syndroms und deren Translation zu einem maternalen Syndrom. Desweiteren wird das Zusammenspiel des maternalen Fettgewebes und der uteroplazentaren Einheit im Hinblick auf die Adipozytokine Leptin und Adiponektin in der Pathologie der Präeklampsie charakterisiert. Übergewichtigkeit stellt einen Risikofaktor für die Präeklampsie dar. Ein weiteres System das in der präeklamptischen uteroplazentaren Einheit dysreguliert ist und das Syndrom in die maternale Zirkulation translatiert, ist das Cytochrom P450 (CYP)-System. Interventionsstudien an zwei Rattenmodellen mit präeklampsieähnlichem Phänotyp verdeutlichen diese Ergebnisse. Ein Rattenmodell aus diesen Studien basiert auf dem RAS und wird in zwei weiteren Arbeiten unserer Gruppe näher charakterisiert. Die Gesamtheit dieser Ergebnisse bietet Erklärungen für die Entstehung der gesteigerten Sensitivität gegenüber Ang II, was in der präeklamptischen Schwangerschaft zu beobachten ist und einen wichtigen Mechanismus der Präeklampsie darstellen könnte. Ebenfalls wird die Bedeutung des systemischen und lokalen RAS in der Pathologie der Präeklamspie verdeutlicht., The pregnancy disorder preeclampsia is a multi-system disorder and the leading cause of maternal morbidity and mortality. Preeclampsia is characterized by increased blood pressure, accompanied by proteinuria. An abnormal placentation leads to an uteroplacental syndrome, which then translates into a maternal syndrome. About 5-10% of all pregnancies worldwide are affected and mothers and children have an increased risk for cardiovascular disease in later life. Objective of this work was to describe fundamental work of our group and to link the described factors and mechanisms. The renin-angiotensin system, the cytochrome P450 system and the adipocytokines are highlighted in this work and the selected publications describe these systems and their underlying mechanisms in preeclampsia.