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Preeclampsia and Increased Permeability Over the Blood–Brain Barrier: A Role of Vascular Endothelial Growth Receptor 2
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics. Department of Clinical Sciences, Sahlgrenska Academy, Gothenburg University , Gothenburg, Sweden;Department of Obstetrics and Gynecology, Stellenbosch University , Stellenbosch, South Africa;Vascular Physiology Laboratory, Department of Basic Sciences, Faculty of Sciences, University of Bío-Bío , Chillán, Chile.ORCID iD: 0000-0001-5202-9428
Vascular Physiology Laboratory, Department of Basic Sciences, Faculty of Basic Sciences, University of Bío-Bío Chillán, Chile..
Vascular Physiology Laboratory, Department of Basic Sciences, Faculty of Basic Sciences, University of Bío-Bío Chillán, Chile..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
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2021 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 34, no 1, p. 73-81Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Cerebral complications in preeclampsia are leading causes of maternal mortality worldwide but the underlying pathophysiology is largely unknown and a challenge to study. Using an in vitro model of the human blood brain barrier (BBB), we explored the role of vascular endothelial growth factor receptor 2 (VEGFR2) in preeclampsia.

METHODS: The human brain endothelial cell line (hCMEC/D3) cultured on Tranwells insert were exposed (12 h) to plasma from women with preeclampsia (n=28), normal pregnancy (n=28) and non-pregnant (n=16) controls. Transendothelial electrical resistance (TEER) and permeability to 70 kDa FITC-dextran were measured for assessment of BBB integrity. We explored possible underlying mechanisms, with focus on expression of tight junction proteins and phosphorylation of two tyrosine residues of VEGFR2, associated with vascular permeability and migration (pY951) and cell proliferation (pY1175). Plasma concentrations of soluble FMS like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured in order to establish correlations with in vitro results.

RESULTS: hCMEC/D3 exposed to plasma from women with preeclampsia exhibited reduced TEER and increased permeability to 70 kDa FITC-dextran. Further, these cells up-regulated the mRNA levels of VEGFR2, as well as pY951-VEGFR2; but reduced pY1175-VEGFR2 (p&0.05 in all cases). No difference in mRNA expression of tight junction protein was observed between gruops. There was no correlation between angiogenic biomarkers and BBB permeability.

CONCLUSION: We present a promising in vitro model of the BBB in preeclampsia. Selective tyrosine phosphorylation of VEGFR2 may participate in the increased BBB permeability in preeclampsia irrespective of plasma concentrations of angiogenic biomarkers.

Place, publisher, year, edition, pages
Oxford University Press, 2021. Vol. 34, no 1, p. 73-81
Keywords [en]
Blood brain barrier, PlGF, VEGFR2, eclampsia, in vitro studies, preeclampsia, sFlt-1
National Category
Gynaecology, Obstetrics and Reproductive Medicine
Identifiers
URN: urn:nbn:se:uu:diva-418582DOI: 10.1093/ajh/hpaa142ISI: 000630199200010PubMedID: 32866228OAI: oai:DiVA.org:uu-418582DiVA, id: diva2:1463355
Funder
Swedish Society of Medicine, SLS-878741Available from: 2020-09-01 Created: 2020-09-01 Last updated: 2025-03-08Bibliographically approved
In thesis
1. Preeclampsia and the brain: The blood-brain barrier and neurological consequences
Open this publication in new window or tab >>Preeclampsia and the brain: The blood-brain barrier and neurological consequences
2025 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cerebral complications of preeclampsia are among the leading causes of maternal mortality. Women with previous preeclampsia and eclampsia have increased long-term risks of cognitive impairment, stroke, and vascular dementia. They report a lower quality of life, concentration issues, and tiredness after childbirth. The pathophysiology of cerebral complications remains unclear, however, is suggested to involve blood-brain barrier (BBB) impairment, loss of cerebral autoregulation, microinfarctions, and edema.

This translational thesis aimed to explore pathophysiological mechanisms of BBB impairment in preeclampsia and to investigate whether preeclampsia and eclampsia increase the risk of neurological disorders and sick leave in the years following childbirth. This was explored through two preclinical laboratory studies and two register-based cohort studies.

The BBB was explored using an in vitro model. Results were correlated to plasma concentrations of cerebral biomarkers. Correlations were estimated with non-parametric tests. Plasma from women with preeclampsia affected the in vitro model of the human BBB by increasing permeability to FITC-Dextran and decreasing transendothelial electrical resistance (TEER) at the cellular level. All cerebral biomarkers were increased in plasma from women with preeclampsia, compared with normotensive pregnancy. Increased plasma concentrations of NfL were correlated to a decrease in TEER over the BBB. Plasma concentrations of tau, NSE and S100B were not associated with TEER.

Associations between gestational hypertension, preeclampsia and eclampsia, and a composite of neurological disorders (migraine, headache, epilepsy, sleep disorders and neurasthenia) were estimated with multivariate Cox regression models. All exposure groups were associated with an increased risk of a composite of neurological disorders, compared with normotensive pregnant women. Gestational hypertension and preeclampsia were associated with increased migraine risk. The strongest association was found between eclampsia and epilepsy.

Associations between preeclampsia and sick leave rates in the second year postpartum were assessed with augmented inverse probability weighting. Women with preeclampsia took more sick leave compared with women without preeclampsia.

In conclusion, plasma from women with preeclampsia impairs BBB function in vitro, and BBB leakage is indicated by correlation between decreased TEER and increased plasma NfL. Women with preeclampsia, particularly eclampsia, face a higher risk of developing neurological disorders postpartum, which may reflect the increased sick leave observed in this group.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2025. p. 90
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2130
Keywords
Preeclampsia, Eclampsia, Blood-Brain Barrier, Cerebral Biomarkers, Neurological Disorders, Sick Leave
National Category
Gynaecology, Obstetrics and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-552137 (URN)978-91-513-2411-1 (ISBN)
Public defence
2025-04-25, Humanistiska Teatern, Engelska Parken, Thunbergsvägen 3C, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2025-04-02 Created: 2025-03-08 Last updated: 2025-04-02Bibliographically approved

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Bergman, LinaFriis, ThereseNelander, MariaWikström, JohanLarsson, AndersWikström, Anna-Karin

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American Journal of Hypertension
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