Preeclampsia and the brain: neural control of cardiovascular changes during pregnancy and neurological outcomes of preeclampsia

Abstract

Preeclampsia (PE) is a form of gestational hypertension that complicates ∼5% of pregnancies worldwide. Over 70% of the fatal cases of PE are attributed to cerebral oedema, intracranial haemorrhage and eclampsia. The aetiology of PE originates from abnormal remodelling of the maternal spiral arteries, creating an ischaemic placenta that releases factors that drive the pathophysiology. An initial neurological outcome of PE is the absence of the autonomically regulated cardiovascular adaptations to pregnancy. PE patients exhibit sympathetic overactivation, in comparison with both normotensive pregnant and hypertensive non-pregnant females. Moreover, PE diminishes baroreceptor reflex sensitivity (BRS) beyond that observed in healthy pregnancy. The absence of the cardiovascular adaptations to pregnancy, combined with sympathovagal imbalance and a blunted BRS leads to life-threatening neurological outcomes. Behaviourally, the increased incidences of maternal depression, anxiety and post-traumatic stress disorder (PTSD) in PE are correlated to low fetal birth weight, intrauterine growth restriction (IUGR) and premature birth. This review addresses these neurological consequences of PE that present in the gravid female both during and after the index pregnancy.

Keywords: disinhibition; hypertension; preeclampsia; pregnancy; sympathovagal imbalance.

Figure 1

The neurological consequences and life-threatening implications of PE. The initial pathophysiology of PE (gray boxes) originates from abnormal remodeling of the spiral arteries at the maternal-placental interface that creates placental ischemia/hypoxia. The ischemic placenta releases inflammatory cytokines, reactive oxygen species, and the anti-angiogenic factor sFlt-1. Furthermore, in the absence of the autonomically regulated cardiovascular adaptations to pregnancy, perturbations in cardiovascular physiology (orange circles) result. The combination of ischemic placental pathogenic factors and the lack of cardiovascular adaptations to pregnancy, lead to cerebrovascular implications (middle red box) that include autoregulatory breakthrough, increased BBB permeability, CSF electrolyte imbalance, BRS impairment, sympathovagal imbalance. The life-threatening consequences (bottom left red box) include white matter lesions, cerebral edema, hemorrhaging infarcts, and eclamptic seizures. Executive dysfunction (bottom middle and right red boxes) include impaired processing speed that can persist for decades after the index pregnancy, delayed recall, and auditory /verbal memory impairments. The behavioral outcomes of depression, anxiety, and PTSD are all significantly associated with low fetal birth weight, IUGR, and premature birth.

Figure 2

GABA_BR-mediated disinhibition of the RVLM as a proposed mechanistic target for future PE studies. Neurons in the dorsomedial regions of the caudal NTS receive and integrate BR afferent inputs. Normally, BR inputs excite these NTS neurons, which in turn, excites the caudal ventrolateral medulla (CVLM). The CVLM reduces sympathetic tone using dual circuitries. First, the CVLM excites preganglionic parasympathetic neurons in the nucleus ambiguus (NA) which projects (via the vagus nerve) to the heart to reduce the heart rate and stroke volume. Secondly, the CVLM projects inhibitory (GABAergic) projections to the “vasomotor center” RVLM. Inhibition of the RVLM reduces the sympathetic tone to the blood vessels, heart, and kidneys. However, in several hypertensive studies, GABA_BR-mediated inhibition of these NTS neurons occurs (expanded synapse in figure). In the presence of AngII, upregulated expression of GABA_BR occurs on NTS neurons. Presynaptically, GABA_BRs inhibit N-type (Ca_V2.2) & P/Q-type (Ca_V2.1) Ca²⁺ channels, and thus reduce the probability of glutamate release into the synaptic cleft. Postsynaptically, GABA_BRs hyperpolarize NTS neurons by activating inward-rectifying K+ channels, inhibiting L-type Ca²⁺ channels, and producing a voltage-sensitive Mg²⁺ block of NMDA receptors, as well as preventing their phosphosphorylation by protein kinase A (PKA). Hyperpolarization of NTS neurons by GABA_BRs result in insufficient excitatory input (dashed arrows) to the NA and CVLM. Decreased parasympathetic input to the heart via the NA results in increases in heart rate and stroke volume. More importantly, the hyperpolarized NTS neurons cannot excite the CVLM, resulting in a disinhibition of the RVLM. No longer governed by the GABAergic tone from the CVLM, the RVLM increases sympathetic tone to the vasculature, heart, and kidneys. Given that PE is characterized by enhanced AngII sensitivity, an impaired BR reflex, and sympathetic overexcitation, this GABA_BR-mediated disinhibition of the RVLM is proposed as a mechanistic target for future PE studies.

Figure 3

Cognitive and behavioral deficits associated with preeclampsia, and their relationship to fetal outcomes. The ischemic placenta releases a myriad of pathogenic factors that lead to endothelial dysfunction. The resulting pathophysiology, if left untreated, can develop into cerebrovascular abnormalities which include a loss of autoregulation, increase in BBB permeability, with a resulting imbalance in CSF electrolyte composition. Collectively, these insults to the CNS can manifest into learning and memory deficits that can persist for decades after the index pregnancy. Moreover, behavioral outcomes of depression, anxiety, and PTSD are significantly associated with low fetal birth weight, IUGR, and preterm birth.