Abstract
Offspring of preeclamptic pregnancies have cognitive alterations. Placental growth factor (PGF), is low in preeclampsia; reduced levels may affect brain development. PGF-null mice differ from normal congenic controls in cerebrovasculature, neuroanatomy and behavior. Using brain imaging and behavioral testing, we asked whether developmentally asynchronous (i.e. neonatal) PGF supplementation alters the vascular, neuroanatomic and/or behavioral status of Pgf−/− mice at adulthood. C57BL/6-Pgf−/− pups were treated intraperitoneally on postnatal days 1–10 with vehicle or PGF at 10 pg/g, 70 pg/g or 700 pg/g. These mice underwent behavioral testing and perfusion for MRI and analysis of retinal vasculature. A second cohort of vehicle- or PGF-treated mice was perfused for micro-CT imaging. 10 pg/g PGF-treated mice exhibited less locomotor activity and greater anxiety-like behavior relative to vehicle-treated mice. Depressive-like behavior showed a sex-specific, dose-dependent decrease and was lowest in 700 pg/g PGF-treated females relative to vehicle-treated females. Spatial learning did not differ. MRI revealed smaller volume of three structures in the 10 pg/g group, larger volume of seven structures in the 70 pg/g group and smaller volume of one structure in the 700 pg/g group. No cerebral or retinal vascular differences were detected. Overall, neonatal PGF replacement altered behavior and neuroanatomy of adult Pgf−/− mice.
Highlights
Serial measurements of maternal plasma across gestation have strongly linked altered pro- and anti-angiogenic signals to the pathogenesis of preeclampsia (PE)
In stark contrast to the critical roles of vascular endothelial growth factor (VEGF) and its signalling via VEGF receptor 2 (VEGFR2) during mouse development, Placental growth factor (PGF) gene deletion is compatible with life
Treated pups weighed significantly less than phosphate buffered saline (PBS)-treated pups (p < 0.05 and p < 0.01, respectively). 10 pg/g PGFtreated pups and PBS-treated pups had similar weights at all time points
Summary
Serial measurements of maternal plasma across gestation have strongly linked altered pro- and anti-angiogenic signals to the pathogenesis of preeclampsia (PE). Offspring of preeclamptic pregnancies (PE-F1s) demonstrate lower scores on cognitive testing as children, young adults or older adults[13,14,15,16,17] These individuals have a higher risk of neuropsychiatric disorders including attention deficit/hyperactivity disorder[18], autism spectrum disorder[19] and depression[20]. A recent study reported impaired brain vascularization in mice after tissue-restricted knockdown of PGF expression in the placenta[27]. Since the neonatal brain is plastic, we questioned if a therapeutic window was present in early life during which angiokine replacement could alter the neuroanatomy and cerebrovasculature in Pgf–/- mouse brains and change adult behavior. The cerebrovasculature, neuroanatomy and behavior of the treated mice were assessed
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