Impacts of Placental Growth Factor Deficiency and of Preeclampsia on Brain Development and Function
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Preeclampsia (PE) is a significant gestational disorder affecting 3-5% of all human pregnancies. In many PE pregnancies, maternal plasma is low in the placentally-produced angiokine “placental growth factor” (PGF). Offspring of PE (PE-F1) compared to uncomplicated pregnancies have higher risks for hypertension, cognitive impairment, and stroke. However, mechanisms explaining these risks are poorly understood. This thesis aimed to explore the mechanistic links between deficient gestational PGF expression, PE, and brain structural and functional development in PE-F1s. It was hypothesized that PGF deficiency, which often manifests in PE, diminishes brain vascular development, leading to impaired cognition and elevated stroke risk postpartum. Uteroplacental angiogenesis was assessed in pregnant mice expressing or lacking maternal and/or conceptus derived PGF by whole-mount immunohistochemistry or paraffin histology. Pgf-/- and Pgf+/+ adult mouse brain vasculature and structural anatomy were examined by arterial polymer casting and magnetic resonance imaging (MRI), respectively. Cognition and behaviour were assessed in these mice by standard paradigms that tested depression, spatial learning, short and long term memory, activity and anxiety. PE-F1 and control children aged 7-10 were assessed for cognitive functions through psychometric testing and eye tracking of saccadic eye movements. Brain structural and vascular anatomy were assessed in the same children through MRI. Pgf-/- mice displayed reduced and aberrant uteroplacental vascular structure, particularly when conceptus-derived PGF was absent. Pgf-/- brain vasculature was deficient and abnormally patterned compared to Pgf+/+ controls. Cognitive and behavioural testing revealed numerous impairments in Pgf-/- mice, with sexually dimorphic differences. MRI revealed structural anatomic differences between the brains of Pgf-/- and Pgf+/+ mice, again with sexually dimorphic differences. In children, PE-F1s displayed deficits in working memory and oculomotor control compared to controls. PE-F1s additionally exhibited altered brain structural and vascular anatomy compared to controls. This work has uncovered a previously unknown link between deficient PGF expression, PE, and brain development in mice and humans. These results have implications for the clinical management of women with PE, as well as their offspring, and underscore the importance of PE prevention.