Abstract
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.
Highlights
According to the International Society for Study of Hypertension in Preeclampsia (ISSHP), preeclampsia is defined as the presence of de novo hypertension (≥140/90 mmHg) after 20 weeks of gestation accompanied by proteinuria and/or a series of systemic symptoms and/or fetal growth restriction (Brown et al, 2018)
We provide a hypothesis of how sFlt-1 could eventually be a protective instead of harmful factor for brain endothelial cells of the blood-brain barrier (BBB), and how it may contribute to the pathophysiology of cerebrovascular complications in preeclampsia based on the current state of the art
In the last two decades, significant advances have been achieved on the study of the cerebrovascular complications of preeclampsia
Summary
According to the International Society for Study of Hypertension in Preeclampsia (ISSHP), preeclampsia is defined as the presence of de novo hypertension (≥140/90 mmHg) after 20 weeks of gestation accompanied by proteinuria and/or a series of systemic symptoms and/or fetal growth restriction (Brown et al, 2018). The hypothesis of endothelial dysfunction mediated by an imbalance between proand anti-angiogenic factors is often discussed assuming that in pregnancy, BBB endothelial cells can adapt to changes in blood VEGF levels through an increase in sFlt-1 as compensatory mechanism This assumption can be misleading as in murine brain endothelial cells, the expression of VEGFR2 is polarized with higher expression in the basolateral side, while VEGFR1 is more expressed in the luminal side, contrary to the observed in lung endothelial cells (Hudson et al, 2014). SFlt-1 and Blood-Brain Barrier Dysfunction pro-inflammatory cytokines including interleukin-1β activate pathways involved in the release of VEGF (Nagineni et al, 2012) In this regard, as ischemic and haemorrhagic stroke are cerebrovascular complications of preeclampsia (McDermott et al, 2018; Too et al, 2018), the paracrine and autocrine activation of VEGFR2 could be responsible of the increased BBB permeability. As most of the presented evidence does not always associate the effects of sFlt-1 on the dynamics of VEGFRs function and its downstream events, this gap in knowledge represents an opportunity to better characterize its actions on pathologies including preeclampsia
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