Preeclampsia and Increased Permeability Over the Blood–Brain Barrier: A Role of Vascular Endothelial Growth Receptor 2

Bergman, Lina; Acurio, Jesenia; Gatu, Emily; Friis, Therese; Nelander, Maria; Wikström, Johan; Larsson, Anders; Lara, Evelyn; Aguayo, Claudio; Torres-Vergara, Pablo; Wikström, Anna‐Karin; Escudero, Carlos

doi:10.1093/ajh/hpaa142

Cited by 26 publications

(33 citation statements)

References 43 publications

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“…In the context of preeclampsia, a study demonstrated that plasma from preeclamptic pregnancies increased the permeability of cerebral rat veins (Amburgey et al, 2010), being this effect counteracted by co-treatment with a VEGFR2 inhibitor. The above outcome is confirmed in human hCMEC/d3 cells, as plasma from preeclamptic pregnancies, apart from increasing the permeability, up-regulated the mRNA expression of VEGFR2 and phosphorylation at the tyrosine residue Y951 (pY951), along with a decreased phosphorylation at the Y1175 (pY1175) residue (Bergman et al, 2021). The above findings agree with those that relate the pY951 with increased endothelial permeability (Matsumoto et al, 2005).…”

Section: Overview Of Vegf Signaling and Its Role On The Cerebrovascul...supporting

confidence: 84%

“…Findings from these studies generally agree that preeclamptic women may suffer some degree of cerebrovascular damage. Recent studies published by our group showed that exposure of hCMEC/d3 cell monolayers (a human brain endothelial cell line) to plasma from preeclamptic pregnancies increased permeability to FITC-dextran 70 kDa and reduced their transendothelial electrical resistance ( Bergman et al, 2021 ; Leon et al, 2021 ), with no changes in tight junction proteins mRNA expression ( Bergman et al, 2021 ).…”

Section: The Blood-brain Barrier In Preeclampsiamentioning

confidence: 99%

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How Soluble Fms-Like Tyrosine Kinase 1 Could Contribute to Blood-Brain Barrier Dysfunction in Preeclampsia?

2022

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Preeclampsia is a pregnancy-related syndrome that courses with severe cerebrovascular complications if not properly managed. Findings from pre-clinical and clinical studies have proposed that the imbalance between pro- and anti-angiogenic factors exhibited in preeclampsia is a major component of its pathophysiology. In this regard, measurement of circulating levels of soluble tyrosine kinase-1 similar to fms (sFlt-1), a decoy receptor for vascular endothelial growth factor (VEGF), is a moderately reliable biomarker for the diagnosis of preeclampsia. However, few studies have established a mechanistic approach to determine how the high levels of sFlt-1 are responsible for the endothelial dysfunction, and even less is known about its effects at the blood-brain barrier (BBB). Since the expression pattern of VEGF receptors type 1 and 2 in brain endothelial cells differs from the observed in peripheral endothelial cells, and components of the neurovascular unit of the BBB provide paracrine secretion of VEGF, this compartmentalization of VEGF signaling could help to see in a different viewpoint the role of sFlt-1 in the development of endothelial dysfunction. In this article, we provide a hypothesis of how sFlt-1 could eventually be a protective factor for brain endothelial cells of the BBB under preeclampsia.

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Section: Overview Of Vegf Signaling and Its Role On The Cerebrovascul...supporting

confidence: 84%

Section: The Blood-brain Barrier In Preeclampsiamentioning

confidence: 99%

How Soluble Fms-Like Tyrosine Kinase 1 Could Contribute to Blood-Brain Barrier Dysfunction in Preeclampsia?

2022

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“…Our group previously reported on in vitro studies of the human brain endothelium, exposed to plasma from women with preeclampsia [ 24 ]. We demonstrated increased permeability and a lower trans endothelial electrical resistance over the in vitro blood–brain barrier after exposure to plasma from women with preeclampsia compared to normotensive women, implicating that plasma from women with preeclampsia induces injury to the blood–brain barrier [ 24 ], supporting the findings from animal studies.…”

Section: Discussionmentioning

confidence: 99%

Evidence of Neuroinflammation and Blood–Brain Barrier Disruption in Women with Preeclampsia and Eclampsia

Bergman

Hastie

Zetterberg

et al. 2021

Cells

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Cerebral complications in preeclampsia are leading causes of maternal mortality. Animal models suggest that an injured blood–brain barrier and neuroinflammation may be important but there is paucity of data from human studies. Therefore, we aimed to evaluate this in women with preeclampsia and eclampsia. We included women recruited to the South African Preeclampsia Obstetric Adverse Events (PROVE) biobank. Blood and cerebrospinal fluid (CSF) were collected around delivery. CSF was analyzed for neuroinflammatory markers interleukin 1β, interleukin 6, interleukin-8 and tumor necrosis factor alpha (TNF-alpha). The CSF to plasma albumin ratio was measured to assess blood–brain barrier function. Women with eclampsia (n = 4) showed increased CSF concentrations of all pro-inflammatory cytokines and TNF-alpha compared to women with normotensive pregnancies (n = 7) and also for interleukin-6 and TNF-alpha compared to women with preeclampsia (n = 4). Women with preeclampsia also showed increases in pro-inflammatory cytokines IL-6 and IL-8 but not TNF-alpha in the CSF compared to women with normotensive pregnancies. In particular, women with eclampsia but also women with preeclampsia showed an increase in the CSF to plasma albumin ratio compared to normotensive women. In conclusion, women with preeclampsia and eclampsia show evidence of neuroinflammation and an injured blood–brain barrier. These findings are seen in particular among women with eclampsia.

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“…Confirmatory experiments of TEER and cell permeability to high-molecular weight fluorescent dye (Fluorescein-5-isothiocyanate FITC-dextran 70 kDa) were performed as previously reported [ 30 ] using randomly selected plasmas from women with preeclampsia (n = 12), and women with normal pregnancies (n = 13).…”

Section: Methodsmentioning

confidence: 99%

“…Up until recently there has been a paucity of studies assessing the human BBB in preeclampsia, due to difficulties in studying the BBB in a clinical setting. However, our research group has recently presented promising results on the human cerebral microvascular endothelial cell line (hCMEC/D3) [ 27 , 28 , 29 ] as a new in vitro model of the BBB in preeclampsia research [ 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

Cerebral Biomarkers and Blood-Brain Barrier Integrity in Preeclampsia

Friis

Wikström

Acurio

et al. 2022

Cells

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Cerebral complications in preeclampsia contribute substantially to maternal mortality and morbidity. There is a lack of reliable and accessible predictors for preeclampsia-related cerebral complications. In this study, plasma from women with preeclampsia (n = 28), women with normal pregnancies (n = 28) and non-pregnant women (n = 16) was analyzed for concentrations of the cerebral biomarkers neurofilament light (NfL), tau, neuron-specific enolase (NSE) and S100B. Then, an in vitro blood–brain barrier (BBB) model, based on the human cerebral microvascular endothelial cell line (hCMEC/D3), was employed to assess the effect of plasma from the three study groups. Transendothelial electrical resistance (TEER) was used as an estimation of BBB integrity. NfL and tau are proteins expressed in axons, NSE in neurons and S100B in glial cells and are used as biomarkers for neurological injury in other diseases such as dementia, traumatic brain injury and hypoxic brain injury. Plasma concentrations of NfL, tau, NSE and S100B were all higher in women with preeclampsia compared with women with normal pregnancies (8.85 vs. 5.25 ng/L, p < 0.001; 2.90 vs. 2.40 ng/L, p < 0.05; 3.50 vs. 2.37 µg/L, p < 0.001 and 0.08 vs. 0.05 µg/L, p < 0.01, respectively). Plasma concentrations of NfL were also higher in women with preeclampsia compared with non-pregnant women (p < 0.001). Higher plasma concentrations of the cerebral biomarker NfL were associated with decreased TEER (p = 0.002) in an in vitro model of the BBB, a finding which indicates that NfL could be a promising biomarker for BBB alterations in preeclampsia.

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Preeclampsia and Increased Permeability Over the Blood–Brain Barrier: A Role of Vascular Endothelial Growth Receptor 2

Cited by 26 publications

References 43 publications

How Soluble Fms-Like Tyrosine Kinase 1 Could Contribute to Blood-Brain Barrier Dysfunction in Preeclampsia?

How Soluble Fms-Like Tyrosine Kinase 1 Could Contribute to Blood-Brain Barrier Dysfunction in Preeclampsia?

Evidence of Neuroinflammation and Blood–Brain Barrier Disruption in Women with Preeclampsia and Eclampsia

Cerebral Biomarkers and Blood-Brain Barrier Integrity in Preeclampsia

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