Male HELLP pups experience sensorimotor delays and reduced body weight

Neurodevelopmental Disruptions in Children of Preeclamptic Mothers: Pathophysiological Mechanisms and Consequences

“…Considering that fetal development is a critical period, an adverse fetal environment such as that occurring in PE can affect neurodevelopmental disorders [40]. The possible pathophysiological mechanisms of neurodevelopmental alterations include hypoxia [32,[40][41][42][43][44][45][46], impairment of vascular function [37,[39][40][41]43,[47][48][49], disturbance in pro-and anti-angiogenic factors [37,[43][44][45][48][49][50], inflammation [32,41,[43][44][45][46]51], exposure to elevated levels of glucocorticoids [47,52], and abnormal placentation [37,39,40,42] (Figure 1), as described below.…”

“…Furthermore, ROS can also negatively regulate calcium-activated potassium channels KCa2.3 and KCa3.1, which are crucial for vasodilation [56][57][58]. Due to the above, a placental ischemic environment is subsequently generated through reducing blood flow in the fetoplacental unit, leading to hypoxia [32,[40][41][42][43][44][45][46]. The hypoxic placenta may secrete altered RNA, along with increased expression levels of hypoxia-inducible factor 1 alpha (HIF-1α) [32,42,59] and placental tumor necrosis factor-alpha (TNF-α) [46,59] as well as an increase in hematocrit [46], which may favor the effects of physiological stress induced by PE and placental hypoxia [32,59].…”

“…In general, neuronal and cerebral vascular development are closely related, and both use the same family of ligands and receptors to regulate important processes that are altered in PE, such as survival, proliferation, angiogenesis, cell organization, cerebral vasculature, and endothelial and neuronal "vascular pruning" processes [69]. PE is associated with alterations in placental pro-and anti-angiogenic factors [43,47,48,50], such as vascular endothelial growth factor (VEGF) [44,46,49], placental growth factor (PGF) [37,44,47,49], soluble fms-like tyrosine kinase 1 receptor (sFlt-1) [37,44,45,47,49], and soluble endoglin (sEng) [70][71][72].…”

“…The dysregulation of sFlt-1 may be one of the factors inducing angiogenic and vascular alterations in PE [37,44,45,47,49]. sFlt-1, also known as soluble vascular endothelial growth factor receptor 1 (sVEGFR1), is a receptor produced by the placenta and is an alternatively spliced version of VEGFR1 (Flt1) with antiangiogenic functions that increase in PE [106][107][108].…”

“…Studies on PE and eclampsia, as well as HELLP, have shown that the levels of sEng and sFlt-1 increase during pregnancy and contribute to the creation of a state of placental inflammation and endothelial dysfunction, along with a decrease in offspring birth weight [45,109]. Endoglin (Eng) is a co-receptor for transforming growth factor β1 and β3 (TGF-β1 and TGF-β3, respectively), and its soluble form derived from the placenta is an antiangiogenic factor that could inhibit TGF-β1 signaling in the vasculature and is related to the etiology of PE [70][71][72]110].…”