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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Avdelningen för obstetrik och gynekologi.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Obstetrisk forskning/Axelsson)
Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Lund, Avdelningen för obstetrik och gynekologi.
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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.

Place, publisher, year, edition, pages
2012. Vol. 18, no 3, p. 146-155
Keywords [en]
angiogenesis, early-onset pre-eclampsia, gene expression, microarray, placenta
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-161107DOI: 10.1093/molehr/gar067ISI: 000300726400005PubMedID: 22013081OAI: oai:DiVA.org:uu-161107DiVA, id: diva2:454474
Available from: 2011-11-07 Created: 2011-11-07 Last updated: 2018-08-19Bibliographically approved
In thesis
1. Preeclampsia – Studies on the Placenta and B-type Natriuretic Peptide
Open this publication in new window or tab >>Preeclampsia – Studies on the Placenta and B-type Natriuretic Peptide
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
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:nbn:se:uu:diva-353295 (URN)978-91-513-0411-3 (ISBN)
Public defence
2018-10-05, Audiotorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 09:15 (Swedish)
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Available from: 2018-09-13 Created: 2018-08-19 Last updated: 2018-10-02

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