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Is Fetal and Placental Size, Blood Pressure and Overall Pregnancy Outcome Determined by Aldosterone Production and Salt Intake?

English title Is Fetal and Placental Size, Blood Pressure and Overall Pregnancy Outcome Determined by Aldosterone Production and Salt Intake?
Applicant Mohaupt Markus
Number 135596
Funding scheme Project funding
Research institution Respiratory Medicine Department Universitätsklinik Inselspital
Institution of higher education University of Berne - BE
Main discipline Clinical Pathophysiology
Start/End 01.09.2011 - 31.08.2014
Approved amount 468'000.00
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All Disciplines (2)

Discipline
Clinical Pathophysiology
Gynaecology

Keywords (4)

Schwangerschaft; Kochsalz; Angiogenese; Aldosteron

Lay Summary (German)

Lead
Lay summary

Welchen Einfluss hat Aldosteron und Salzzufuhr auf die Plazentagrösse, das Geburtsgewicht und den Schwangerschaftsverlauf einschliesslich des mütterlichen Blutdrucks?

Eine sogenannte Schwangerschaftsvergiftung, auch Präeklampsie genannt, ist eine lebensbedrohliche Erkrankung für Mutter und Kind in der Schwangerschaft. Die Hauptsymptome, Bluthochdruck und Eiweissausscheidung im Urin, sind Folge der durch die Erkrankung in der Folge ausgelösten Schädigung der Gefässbinnenhaut, dem Endothel. Die Erkrankung ist multifaktoriell, jedoch sprechen verschiedene Befunde dafür, dass das Hormon Aldosteron, welches das Salz- und Wassergleichgewicht im Körper herstellt, auch für die Vermehrungsfunktion wichtig ist. Bereits menstruationszyklusabhängig, aber besonders ausgeprägt in der Schwangerschaft steigt dieses Hormon an und trägt zum Flüssigkeitshaushalt und der Wahrung der Plazentadurchblutung bei.

Bei einer Präeklampsie ist das Blutvolumen vermindert, paradoxerweise steigt das Aldosteron jedoch nicht an, sondern ist deutlich vermindert. Dafür ist bei einem Teil der Frauen ein genetischer Defekt verantwortlich. Wenn hierdurch die Plazenta schlechter durchblutet wird, sendet diese Entzündungs- und gefässschädigende Signale in die mütterliche Blutbahn. Dadurch wird das Endothel der Gefässe geschädigt, Flüssigkeit kann schlechter in den Gefässen gehalten werden und die Erkrankung nimmt ihren Lauf. Interessanterweise finden sich Effekte des Aldosterons über eine reine Volumenregulation hinaus. Ich konnte zeigen, dass Aldosteron das Plazentawachstum stimuliert, ein Effekt der sich auch in Tiermodellen und beim Menschen findet. Darüberhinaus kommt es im Tiermodell bei einer Aldosteronhemmung sogar zu einer Beeinträchtigung der Durchblutung des ungeborenen Kindes.

Aldosteron ist dann wichtig, wenn Natrium im Körper zurückgehalten werden muss. Untersuchungen von mir und von anderen Autoren zeigen, dass eine hohe Kochsalzzufuhr in der Schwangerschaft die Anzahl mütterlicher und kindlicher Komplikationen sowie den Blutdruck senken konnte. Diese Beobachtungen unterstützen die Annahme, dass ein hohes Plasmavolumen für eine intakte Schwangerschaft wichtig ist.

Um diesen Fragen beim Menschen nachgehen zu können, habe ich in Bern in Zusammenarbeit mit der Klinik für Geburtshilfe eine Schwangerschaftsdaten- und –biobank etabliert.

Ich stelle daher die Theorie auf, das seine ausreichende Verfügbarkeit von Aldosteron und Kochsalz in der Schwangerschaft ein Gleichgewicht eingehen müssen, um die kindliche Versorgung sicherzustellen. Dabei stellt ein Plazentawachstum durch eine gesteigerte Aldosteronwirkung die Versorgung des Kindes auch bei Salzmangel sicher. Eine ausreichende Salzversorgung könnte jedoch auch bei einer kleineren Plazenta eine ausreichende fetale Entwicklung und somit ein normales Schwangerschaftsergebnis sicherstellen. Ich erwarte die bedrohlichste Situation, wenn bei hoher Kochsalzzufuhr zu Beginn der Schwangerschaft die Plazenta klein bleibt und die Mutter im späteren Verlauf der Schwangerschaft einem Salzmangel ausgesetzt wird, auf den sie dann nicht vorbereitet ist. Daher soll speziell

erstens die Aldosteronsynthese in Abhängigkeit von der Kochsalzzufuhr bei Schwangeren untersucht werden,

zweitens die begleitende Angiogeneseregulation abgeschätzt werden,

drittens genetische Störungen der Aldosteronproduktion untersucht werden, und

viertens die Interaktion von Schwangerschaft, Kochsalzzufuhr, Aldosteronproduktion und Angiogenese in einem Tiermodell untersucht werden, bei welchem die Tiere hoher, tiefer und hoher und anschliessend tiefer Kochsalzernährung ausgesetzt werden.

Zukünftig könnte bei günstigen Ergebnissen versucht werden, schwangeren Frauen vermehrt Kochsalz zuzuführen, um den Schwangerschaftsverlauf erfolgreich zu gestalten.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Name Institute

Employees

Publications

Publication
Cholesterol acceptor capacity is preserved by different mechanisms in preterm and term fetuses
Pecks Ulrich, Mohaupt Markus G., Hütten Matthias C., Maass Nicolaì, Rath Werner H., Escher Geneviève (2014), Cholesterol acceptor capacity is preserved by different mechanisms in preterm and term fetuses, in Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1841(2), 251-258.
Normotensive blood pressure in pregnancy: The role of salt and aldosterone
Gennari-Moser Carine, Escher Geneviève, Kramer Simea, Dick Bernhard, Eisele Nicole, Baumann Marc U., Raio Luigi, Frey Felix J., Surbek Daniel V., Mohaupt Markus G. (2014), Normotensive blood pressure in pregnancy: The role of salt and aldosterone, in Hypertension, 63(2), 362-368.
Primary male osteoporosis is associated with enhanced glucocorticoid availability
Arampatzis Spyridon, Pasch Andreas, Lippuner Kurt, Mohaupt Markus (2013), Primary male osteoporosis is associated with enhanced glucocorticoid availability, in RHEUMATOLOGY, 52(11), 1983-1991.
Response to are aldosterone levels inappropriately low in preeclampsia?
Gennari-Moser Carine, Khankin Eliyahu V., Escher Geneviève, Burkhard Fiona C., Frey Brigitte M., Karumanchi S. Ananth, Frey Felix J., Mohaupt Markus G. (2013), Response to are aldosterone levels inappropriately low in preeclampsia?, in Hypertension, 62(5), 40-40.
Vascular endothelial growth factor- A and aldosterone: Relevance to normal pregnancy and preeclampsia
Gennari-Moser Carine, Khankin Eliyahu V., Escher Geneviève, Burkhard Fiona C., Frey Brigitte M., Karumanchi S. Ananth, Frey Felix J., Mohaupt Markus G. (2013), Vascular endothelial growth factor- A and aldosterone: Relevance to normal pregnancy and preeclampsia, in Hypertension, 61(5), 1111-1117.
Aldosterone deficiency adversely affects pregnancy outcome in mice
Todkar Abhijeet P., Chiara Marianna Di, Loffing-Cueni Dominique, Bettoni Carla, Mohaupt Markus G., Loffing Johannes A N, Wagner Carsten Alexander (2012), Aldosterone deficiency adversely affects pregnancy outcome in mice, in Pflugers Archiv European Journal of Physiology, 464(4), 331-343.
Regulation of placental growth by aldosterone and cortisol
Gennari-Moser Carine, Khankin Eliyahu V., Schüller Simone, Escher Geneviève, Frey Brigitte M., Portmann Carol Bettina, Baumann Marc U., Lehmann Andrea D., Surbek Daniel V., Karumanchi S. Ananth, Frey Felix J., Mohaupt Markus G. (2011), Regulation of placental growth by aldosterone and cortisol, in Endocrinology, 152(1), 263-271.

Collaboration

Group / person Country
Types of collaboration
Prof.Dr. D. Surbek, Frauenklinik der Universität Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Dr. U. Pecks, Universität Aachen, Deutschland Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof.Dr. F. Burkhard, Inselspital, Urologie, Bern Switzerland (Europe)
- Publication
- Research Infrastructure
Prof.Dr. C: Wagner, Institute of Physiology, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof.Dr. A. Karumanchi, BIDMC, Harvard Medical School, Boston United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Schweizerische Gesellschaft für Nephrologie Talk given at a conference Role of aldosterone in pregnancy 05.12.2013 Interlaken, Switzerland Eisele Nicole; Mohaupt Markus; Jain Kanika;
International Society for the Study of Hypertension in Pregnancy Talk given at a conference Role of Aldosterone in Pregnancy and Preeclampsia 09.07.2012 Genf, Switzerland Eisele Nicole; Mohaupt Markus; Pecks Ulrich;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Salz in der Schwangerschaft Verschiedene schweizerische Zeitungen und Zeitschrift Eltern International German-speaking Switzerland 2014

Awards

Title Year
Best Poster award ISSHP 2012 2012

Associated projects

Number Title Start Funding scheme
156830 Salt Supplementation in Pregnancies at High Risk to Develop Preeclampsia - Clinical Outcome and Molecular Prediction of Response 01.02.2015 Project funding
113902 Evaluation of Aldosterone Production/Salt Sensitivity in Early Pregnancy 01.12.2006 Project funding
156830 Salt Supplementation in Pregnancies at High Risk to Develop Preeclampsia - Clinical Outcome and Molecular Prediction of Response 01.02.2015 Project funding
150823 Serial block face SEM 01.12.2013 R'EQUIP

Abstract

Preeclampsia is a life-threatening disease in pregnancy presenting a major health threat for mother and child. The clinical phenotype including arterial hypertension and proteinuria are currently attributed to disturbed angiogenic signaling and endothelial integrity. The causes for the dysbalance are under discussion with increased consideration of contributing factors other than just disturbed placental implantation. In this regard the importance of aldosterone and activation of its respective effector, the mineralocorticoid receptor, appeared in animals departing salt water for a dry and salt-deprived environment. Thus, the first and most prominent role of aldosterone was attributed to the maintenance of volume homeostasis by reabsorbing sodium. More recently, evidence was presented that aldosterone which already rises in the luteal phase of the menstrual cycle and, if a conception occurs, increases by a factor of 20 throughout pregnancy towards term. It is believed that this is an adaptive mechanism to expand the plasma volume allowing for an appropriate utero-placental perfusion. In preeclampsia, for reasons only partially understood, plasma volume and placental size are reduced while aldosterone levels are low suggesting a new functional relationship. In a subset of preeclamptic women aldosterone production is compromised by a loss-of-function mutant of the aldosterone synthase while gain-of-function mutants seem to protect from hypertensive pregnancies. The diminished aldosterone levels of preeclampsia despite a reduced plasma volume are thought to further advance into a vicious cycle by compromising utero-placental perfusion and rather enhancing the secretion of antiangiogenic mediators. A model of adrenalectomized animals even suggested a relationship of placental growth with Aldo availability, a finding supported by own data of the applicant. Compromised aldosterone production would such not only limit plasma volume, but also placental growth, a feature of preeclamptic pregnancies. It is known from other clinical situations that aldosterone deficiency can be counterbalanced by NaCl supplementation. Therefore, NaCl supplementation might be beneficial in pregnant women with impaired aldosterone synthesis, an assumption supported with respect to plasma volume expansion by previous observations in pregnant women from us and others. In these investigations, the blood pressure response profited from plasma volume expansion through enhanced sodium availability. The clinically observed sequence of intravascular volume depletion causing placental ischemia with subsequently increased maternal blood pressure would thus clearly support the concept that a high maternal cardiac output facilitated by plasma volume expansion and sufficient placental perfusion is mandatory for fetal well-being.In the past, in close collaboration with Prof. Surbek, the head of obstetrics at our institution, I have established a pregnancy data and biobank (the Berne pregnancy register) which is ever expanding, and which already allows access to several hundred individual cases and biosamples.I hypothesize now that high aldosterone availability and high sodium intake counterbalance each other throughout pregnancy supporting a well-developed and functioning feto-placental unit. I expect the impact of sodium depletion to enhance compensatory placental growth and of sodium excess to be accompanied by a smaller placenta size but still a maintained appropriate fetal development in healthy pregnancies. The most critical condition is expected to be a high sodium intake initially followed by sodium deprivation in the presence of a rather small placenta due to low aldosterone concentrations. Therefore, I propose specificallyfirst, to assess the apparent aldosterone synthase activity with its rate limiting step 18-methyloxidase activity by measuring the urinary ratios of DOC and total DOC to TH-Aldo and 18-OH-THA to TH-Aldo as well as total TH-Aldo by GC-MS longitudinally in relation to salt intake as assessed by 24-h urinary Na excretion and to ultrasound-based follow-up of uterine, fetal and placental parameters in 300 pregnant women throughout pregnancy; second, to assess serum aldosterone, free VEGF and sFlt-1 levels in regular and preeclamptic pregnant women longitudinally along pregnancy;third, to analyze the aldosterone synthase gene including the promoter region for polymorphisms associated with an altered function (loss and/or gain) in the pregnant women; andforth, to assess a pregnant rat animal model with respect to placental size, fetal development and aldosterone production with either a extreme low sodium or a high sodium diet in addition to a sequential exposure to first a high sodium diet followed by a low sodium diet.Rationale and future directions (not part of this proposal): If my hypothesis proofs to be correct this would be the basis for a randomized placebo controlled prospective study in collaboration with my colleagues from obstetrics focusing on the prevention of arterial hypertension, preeclampsia and/or small-for-gestational date babies by high NaCl intake in pregnant women with or without a reduced aldosterone availability. The proposed data are absolutely required despite already present encouraging data since an enormous reluctance exists to change the paradigm of limiting salt intake during pregnancy.
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