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Preeclampsia – Studies on the Placenta and B-type Natriuretic Peptide
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Reproduktionsbiologi, Reproductive Biology)ORCID iD: 0000-0003-4088-400X
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Preeclampsia has several pathophysiological pathways, but the placenta has a central role. The pathophysiology appears to differ between the two subtypes – early- and late-onset preeclampsia. In clinically evident preeclampsia, maternal circulatory levels of the cardiac peptide B-type natriuretic peptide (BNP) and its cleavage fragment NT-proBNP are elevated, but whether or not the peptides are involved in the pathophysiology of preeclampsia is unknown. The overall aim of the current work was to expand knowledge of preeclampsia pathophysiology, with a main focus on the relationship between BNP and NT-proBNP, and early- and late-onset preeclampsia.

In Paper I, the placental transcriptional profiles of early- and late-onset preeclampsia were compared by using microarrays and bioinformatics. A total of 196 transcripts were differently regulated in the two groups. Using qRT-PCR, mRNA levels of the two angiogenesis-related transcripts ACVRL1 and EGFL7 were confirmed to be lower in early-onset preeclampsia than in both late-onset preeclampsia and early controls.

In Paper II, the circulatory levels of NT-proBNP were higher in both early- and late-onset preeclampsia than in gestational age-matched controls. BNP mRNA and protein were detected by qRT-PCR and immunohistochemistry in placentas from both women with preeclampsia and controls.

In Paper III, circulatory levels of NT-proBNP were measured in the early second-trimester in women who later developed early-onset preeclampsia and in women who continued to have normal pregnancies. No differences were found between the two groups of women.

In Paper IV, the secretion of NT-proBNP, and the mRNA levels of BNP and BNP receptors were investigated in cultured primary trophoblasts. Low levels of NT-proBNP were found in the supernatants of term but not first-trimester trophoblasts. BNP and BNP-receptor mRNA were detected in term trophoblasts.

The results of this work strengthen the concept of the two subtypes of preeclampsia (early- and late-onset) having partly different pathophysiological pathways. The results also indicate that the placenta releases BNP and that BNP may have receptor-mediated effects on the placenta.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. , p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1487
Keywords [en]
BNP, B-type natriuretic peptide, early-onset preeclampsia, gene expression, NT-proBNP, placenta, preeclampsia, trophoblasts
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
URN: urn:nbn:se:uu:diva-353295ISBN: 978-91-513-0411-3 (print)OAI: oai:DiVA.org:uu-353295DiVA, id: diva2:1239906
Public defence
2018-10-05, Audiotorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2018-09-13 Created: 2018-08-19 Last updated: 2018-10-02
List of papers
1. Gene expression profiling of placentae from women with early- and late-onset pre-eclampsia: down-regulation of the angiogenesis related genes ACVRL1 and EGFL7 in early-onset disease
Open this publication in new window or tab >>Gene expression profiling of placentae from women with early- and late-onset pre-eclampsia: down-regulation of the angiogenesis related genes ACVRL1 and EGFL7 in early-onset disease
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2012 (English)In: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 18, no 3, p. 146-155Article in journal (Refereed) Published
Abstract [en]

The underlying mechanisms behind the obstetric condition pre-eclampsia (PE) are still unclear. Manifestation of PE is heterogeneous and it has therefore been proposed to be a syndrome with different causes rather than one disease with a specific aetiology. Recently, we showed differences in circulating angiogenic factors between two subgroups - early- and late-onset PE. To further elucidate the differences between the two, we investigated placental gene expression profiles. Whole genome microarray technology and bioinformatic analysis were used to evaluate gene expression profiles in placentae from early- (24-32 gestational weeks, n=8) and late-onset (36-41 gestational weeks, n=7) PE. The results were verified by using quantitative real-time PCR. We found significant differences in the expression of 196 genes in early- compared with late-onset PE, 45 of these genes showing a fold change above 2. Bioinformatic analysis revealed alterations in angiogenesis and regulation of cell motility. Two angiogenesis-associated transcripts (Egfl7 and Acvrl1) showed lower expression in early-onset PE vs. late-onset PE (p=0.037 and p=0.003) and vs. gestational age-matched controls (p=0.007 and p=0.011). We conclude that angiogenesis-associated genes are regulated in a different manner in the two subgroups, and that the gene expression profiles of early- and late-onset PE diverge, supporting the hypothesis of early- and late-onset PE being at least partly two separate entities.

Keywords
angiogenesis, early-onset pre-eclampsia, gene expression, microarray, placenta
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-161107 (URN)10.1093/molehr/gar067 (DOI)000300726400005 ()22013081 (PubMedID)
Available from: 2011-11-07 Created: 2011-11-07 Last updated: 2018-08-19Bibliographically approved
2. Placental Expression of proBNP/NT-proBNP and Plasma Levels of NT-proBNP in Early- and Late-Onset Preeclampsia
Open this publication in new window or tab >>Placental Expression of proBNP/NT-proBNP and Plasma Levels of NT-proBNP in Early- and Late-Onset Preeclampsia
2014 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 27, no 9, p. 1225-1230Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Levels of plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) are elevated in preeclampsia. In this study, the possibility that the placenta produces and releases proBNP/NT-proBNP was explored. Plasma levels of NT-proBNP in early- and late-onset preeclampsia were also measured.

METHODS: Placental proBNP mRNA in early-onset preeclampsia (n = 7), late-onset preeclampsia (n = 8), and controls of similar gestational age (n = 10) was assessed by quantitative real-time polymerase chain reaction. ProBNP/NT-proBNP protein was studied in placental samples with immunohistochemistry (n = 8) and tissue culture (n = 2). Plasma levels of NT-proBNP were measured in early-onset preeclampsia (n = 18), late-onset preeclampsia (n = 20), and relevant controls (n = 36).

RESULTS: Transcripts of proBNP mRNA were found in 20 out of 25 samples, there were no differences in expression between the groups. ProBNP/NT-proBNP protein was observed in maternal spiral arteries and in syncytiotrophoblasts in all placental samples. After placental tissue culture, there were measurable amounts of NT-proBNP in the culture media. Women with both early- (365 [14-9815] pg/ml) and late-onset preeclampsia (176 [33-2547] pg/ml) had higher levels of NT-proBNP than their controls (P < 0.001). There was a tendency toward higher levels of NT-proBNP in women with early-onset preeclampsia than in women with late-onset preeclampsia (P = 0.057).

CONCLUSION: The results indicate possible placental production and release of proBNP/NT-proBNP into the maternal circulation.

National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-220510 (URN)10.1093/ajh/hpu033 (DOI)000342853700014 ()24610898 (PubMedID)
Available from: 2014-03-17 Created: 2014-03-17 Last updated: 2018-08-19Bibliographically approved
3. Early second-trimester plasma levels of NT-proBNP in women who subsequently develop early-onset preeclampsia
Open this publication in new window or tab >>Early second-trimester plasma levels of NT-proBNP in women who subsequently develop early-onset preeclampsia
2017 (English)In: The Journal of Maternal-Fetal & Neonatal Medicine, ISSN 1476-7058, E-ISSN 1476-4954, Vol. 30, no 18, p. 2163-2165Article in journal (Refereed) Published
Abstract [en]

Plasma levels of NT-proBNP are elevated in women with preeclampsia at the time of diagnosis. The objective of this case-control study was to evaluate N-terminal proBNP (NT-proBNP) in maternal plasma as an early second-trimester biomarker for prediction of early-onset preeclampsia. In early second-trimester samples, women who later developed preeclampsia at gestational age 34 wk + 0 or earlier (n = 16) had similar plasma levels of NT-proBNP (median 51.8, range 26.1-131.9 pg/ml) as women with uncomplicated pregnancy outcomes (n = 43) (53.0, 14.9-184.2 pg/ml). The early second-trimester level of NT-proBNP cannot therefore be used as a predictive biomarker of early-onset preeclampsia.

Place, publisher, year, edition, pages
Taylor & Francis, 2017
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-305825 (URN)10.1080/14767058.2016.1241992 (DOI)000405217100005 ()27677676 (PubMedID)
Available from: 2016-10-22 Created: 2016-10-22 Last updated: 2018-08-19Bibliographically approved
4. Primary Term Trophoblasts Release NT-proBNP
Open this publication in new window or tab >>Primary Term Trophoblasts Release NT-proBNP
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(English)Manuscript (preprint) (Other academic)
Keywords
B-type natriuretic petide, cell culture, NT-proBNP, placenta, trophoblasts
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:uu:diva-353326 (URN)
Available from: 2018-08-18 Created: 2018-08-18 Last updated: 2018-08-19

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