A Longitudinal Pilot Study on Cognition and Cerebral Hemodynamics in a Mouse Model of Preeclampsia Superimposed on Hypertension: Looking at Mothers and Their Offspring

Abstract

Preeclampsia is a common hypertensive disorder in pregnant women and whose causes and consequences have focused primarily on cardiovascular outcomes on the mother and offspring, often without taking into consideration the possible effects on the brain. One possible cause of preeclampsia has been attributed to alterations in the renin-angiotensin system, which has also been linked to cognitive decline. In this pilot study, we use a transgenic mouse model that chronically overexpresses human angiotensinogen and renin (R+A+ mice) that displayed characteristics of preeclampsia such as proteinuria during gestation. Offspring of these mothers as well as from control mothers were also examined. We were primarily interested in detecting whether cognitive deficits were present in the mothers and offspring in the long term and used a spatial learning and memory task as well as an object recognition task at three timepoints: 3, 8, and 12 months post-partum or post-natal, while measuring blood pressure and performing urine analysis after each timepoint. While we did not find significant deficits in preeclamptic mothers at the later timepoints, we did observe negative consequences in the pups of R+A+ mice that coincided with hemodynamic alterations whereby pups had higher whisker-evoked oxygenated hemoglobin levels and increased cerebral blood flow responses compared to control pups. Our study provides validation of this preeclampsia mouse model for future studies to decipher the underlying mechanisms of long-term cognitive deficits found in offspring.

Reduced Brain Cortex Angiogenesis in the Offspring of the Preeclampsia-Like Syndrome

“…Nevertheless, our results contrast with another study in adult offspring (12 months of age) of PELS generated in transgenic female mice overexpressing human angiotensinogen and renin, which showed increased cerebral blood flow in response to whisker stimulation. 44 The apparent disparity between these findings may be associated with differences in the PELS model used to study the offspring. In this regard, to overcome the potential bias generated using L-NAME, we confirmed the finding of reduced brain angiogenesis in 2 additional mouse models, the RUPP model 10 and the genetic C1q model of preeclampsia.…”

Experimental Preeclampsia Causes Long-Lasting Hippocampal Vascular Dysfunction and Memory Impairment

“…A recent study investigating maternal cognitive function after PE in a mouse model reported findings that contradict those of the current study. Trigiani et al (2021) investigated post-partum cognitive function and cerebral hemodynamics in a transgenic mouse model overexpressing human angiotensinogen and renin (R + A + model of PE) ( Trigiani et al, 2021 ). They showed that hippocampal-dependent memory function remained unaffected at 3, 8 and 12 months post-partum, as tested using Morris water maze and NOR ( Trigiani et al, 2021 ).…”

“…Trigiani et al (2021) investigated post-partum cognitive function and cerebral hemodynamics in a transgenic mouse model overexpressing human angiotensinogen and renin (R + A + model of PE) ( Trigiani et al, 2021 ). They showed that hippocampal-dependent memory function remained unaffected at 3, 8 and 12 months post-partum, as tested using Morris water maze and NOR ( Trigiani et al, 2021 ). Given that the R + A + mouse model of PE did not demonstrate impaired hippocampal function several months post-partum suggests that the differing mechanisms used to induce the PE models likely contributes to the discrepancy in findings.…”