Are the Cognitive Alterations Present in Children Born From Preeclamptic Pregnancies the Result of Impaired Angiogenesis? Focus on the Potential Role of the VEGF Family

Abstract

Evidence from clinical studies has proposed that children born from preeclamptic women have a higher risk of suffering neurological, psychological, or behavioral alterations. However, to date, the mechanisms behind these outcomes are poorly understood. Here, we speculate that the neurodevelopmental alterations in the children of preeclamptic pregnancies result from impaired angiogenesis. The pro-angiogenic factors vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are key regulators of both vascular and neurological development, and it has been widely demonstrated that umbilical blood of preeclamptic pregnancies contains high levels of soluble VEGF receptor type 1 (sFlt-1), a decoy receptor of VEGF. As a consequence, this anti-angiogenic state could lead to long-lasting neurological outcomes. In this non-systematic review, we propose that alterations in the circulating concentrations of VEGF, PlGF, and sFlt-1 in preeclamptic pregnancies will affect both fetal cerebrovascular function and neurodevelopment, which in turn may cause cognitive alterations in post-natal life.

Keywords: angiogenesis; neurocognitive; neurovascular; placental growth factor; preeclampsia; sFlt-1; vascular endothelial growth factor.

FIGURE 1

Proposed model of alterations in brain vascular development in offspring born to preeclampsia. Vascular system components in the cerebral cortex emerge directly or indirectly from the pial capillary anastomotic plexus located in the pial lamella (the inner meningeal compartment). The microvascular compartment in the brain cortex is a key component not only for the blood brain barrier but also for cortex development itself. The process of microvasculature formation in the human brain cortex, in which both new vessel formation (angiogenesis) and vascular remodeling takes place, is highly dynamic and not totally understood. Vessel formation in the brain cortex starts during fetal development and continues in the post-natal stage. It is proposed that in the elderly, cortical vessel formation decreases and/or vascular remodeling increases. Since preeclampsia is characterized by an imbalance in pro and anti-angiogenic markers, it has been speculated that cerebral angiogenesis is altered in children born to mothers with preeclampsia. This alteration might be present throughout life, and may explain the greater risk of cognitive alterations in these individuals. The figure is reproduced with permission from the copyright holder.

FIGURE 2

VEGFR1 and VEGFR2 in brain vessel formation. (A) The extent of perfusion of brain tissue depends on both angiogenesis and vascular remodeling processes, which are mediated by pro- and anti-angiogenic factors. (B) VEGF and PlGF activate VEGFR1 and VEGFR2. Phosphorylation of tyrosine 951 (Y951) or Y1175 is associated with activation of VEGFR2, leading preferentially to cell migration or cell proliferation, respectively. These regulatory mechanisms are involved in angiogenesis and neuronal survival. In contrast, sFlt-1 prevents the binding of VEGF and PlGF to VEGFRs, thus decreasing their pro-angiogenic and neuronal survival activity. In this manuscript it is postulated that children born to preeclampsia exhibit a reduced number of blood vessels in the brain cortex, through impaired angiogenesis and/or increased vascular remodeling. We also propose that the underling mechanism might involve dysregulation in VEGFR2 activation due to high sFlt-1 circulating levels in preeclampsia.