Placental Growth Factor Modulates Vascularization and Neuroanatomy in Mice
Preeclampsia (PE) is a common pregnancy complication and may result in fetal stress with lifelong consequences for cognition. Offspring cognitive alterations are associated with distorted neuroanatomy and cerebrovasculature. Although the pathophysiology is complex, reduced expression of pro-angiogenic factors may result in impaired fetal vascularization, altered brain structure and impaired cognition. In particular, low concentrations of placental growth factor (PGF) may alter neural development. Pgf -/- mice were used to interrogate the role of PGF in central nervous system vascularization, appropriate neuroanatomy and behaviour. Subsequently, Pgf -/- mice were used to investigate the postnatal period as a window for intervention. Pgf -/- mice were hypothesized to have impaired cerebrovascular development with permanent deviations of the cerebrovasculature, neuroanatomy and behaviour. Adult deficits were hypothesized to be correctable with an early postnatal PGF treatment. Whole-mount immunofluorescence of the brain and retina examined vascularization and circle of Willis connectivity. Micro-CT imaging visualized the entire cerebrovasculature in adult mice. Magnetic resonance imaging determined the volume of 62 unique structures in the adult mouse brain. Behavioural testing of adult mice examined spatial learning, object recognition, depressive-like behaviour and anxiety-like behaviour. As a postnatal treatment, recombinant PGF was administered to Pgf -/- mice from postnatal day 1-10 before examination of the cerebrovasculature, neuroanatomy and behaviour in adulthood. Pgf -/- mice exhibited delayed vascularization of the hindbrain, less connectivity of the circle of Willis and altered arteriovenous organization in the retina. In adulthood, more small-diameter cerebral vessels were present and 10/62 structures in the brain had smaller volume. On behavioural testing, Pgf -/- mice exhibited poorer performance on spatial learning tests but better performance on depressive-like behaviour and object recognition tests relative to Pgf +/+ controls. Postnatal PGF treatment altered adult neuroanatomy and behaviour but not the cerebrovasculature. In particular, treatment with 70 pg/g PGF partially corrected alterations seen in Pgf -/- mice. Overall, PGF is important for cerebrovascular development, adult neuroanatomy and cognitive behaviour in mice. PGF deficiency may be one factor in a PE-gestation that leads to altered offspring brain development. Finally, the postnatal period is a potential time for intervention in offspring after PE-impacted gestation.