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1.
Physiol Genomics ; 50(10): 862-875, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30118404

RESUMO

Preeclampsia, a hypertensive syndrome occurring in 3-5% of human pregnancies, has lifelong health consequences for fetuses. Cognitive ability throughout life is altered, and adult stroke risk is increased. One potential etiological factor for altered brain development is low concentrations of proangiogenic placental growth factor (PGF). Impaired PGF production may promote an antiangiogenic fetal environment during neural and cerebrovascular development. We previously reported delayed vascularization of the hindbrain, altered retinal vascular organization, and less connectivity in the circle of Willis in Pgf-/- mice. We hypothesized Pgf-/- mice would have impaired cognition and altered brain neuroanatomy in addition to compromised cerebrovasculature. Cognitive behavior was assessed in adult Pgf-/- and Pgf+/+ mice by four paradigms followed by postmortem high-resolution MRI of neuroanatomy. X-ray microcomputed tomography imaging investigated the three-dimensional cerebrovascular geometry in another cohort. Pgf-/- mice exhibited poorer spatial memory, less depressive-like behavior, and superior recognition of novel objects. Significantly smaller volumes of 10 structures were detected in the Pgf-/- compared with Pgf+/+ brain. Pgf-/- brain had more total blood vessel segments in the small-diameter range. Lack of PGF altered cognitive functions, brain neuroanatomy, and cerebrovasculature in mice. Pgf-/- mice may be a preclinical model for the offspring effects of low-PGF preeclampsia gestation.


Assuntos
Encéfalo/diagnóstico por imagem , Neuroanatomia , Fator de Crescimento Placentário/deficiência , Aprendizagem Espacial/fisiologia , Microtomografia por Raio-X/métodos , Animais , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/embriologia , Encéfalo/irrigação sanguínea , Encéfalo/embriologia , Cognição , Feminino , Humanos , Masculino , Memória , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Crescimento Placentário/genética , Gravidez
2.
Placenta ; 48 Suppl 1: S40-S46, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-26880207

RESUMO

Preeclampsia (PE) is a significant gestational disorder affecting 3-5% of all human pregnancies. In many PE pregnancies, maternal plasma is deficient in placental growth factor (PGF), a placentally-produced angiokine. Beyond immediate fetal risks associated with acute termination of the pregnancy, offspring of PE pregnancies (PE-F1) have higher long-term risks for hypertension, stroke, and cognitive impairment compared to F1s from uncomplicated pregnancies. At present, mechanisms that explain PE-F1 gains in postpartum risks are poorly understood. Our laboratory found that mice genetically-deleted for Pgf have altered fetal and adult brain vascular development. This is accompanied by sexually dimorphic alterations in anatomic structure in the adult Pgf-/- brain and impaired cognitive functions. We hypothesize that cerebrovascular and neurological aberrations occur in fetuses exposed to the progressive development of PE and that these brain changes impair cognitive functioning, enhance risk for stroke, elevate severity of stroke, and lead to worse stroke outcomes. These brain and placental outcomes may be linked to down-regulated PGF gene expression in early pre-implantation embryos, prior to gastrulation. This review explores our hypothesis that there are mechanistic links between low PGF detection in maternal plasma prodromal to PE, PE, and altered brain vascular, structural, and functional development amongst PE-F1s. We also include a summary of preliminary outcomes from a pilot study of 7-10 year old children that is the first to report magnetic resonance imaging, magnetic resonance angiography, and functional brain region assessment by eye movement control studies in PE-F1s.


Assuntos
Encéfalo/crescimento & desenvolvimento , Cognição/fisiologia , Fator de Crescimento Placentário/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Trofoblastos/metabolismo , Distinções e Prêmios , Encéfalo/metabolismo , Feminino , Humanos , Gravidez
3.
Behav Brain Res ; 302: 175-81, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26784561

RESUMO

Preeclampsia (PE) is a significant clinical disorder occurring in 3-5% of all human pregnancies. Offspring of PE pregnancies (PE-F1s) are reported to exhibit greater cognitive impairment than offspring from uncomplicated pregnancies. Previous studies of PE-F1 cognitive ability used tests with bias that do not assess specific cognitive domains. To improve cognitive impairment classification in PE-F1s we used standardized clinical psychometric testing and eye tracking studies of saccadic eye movements. PE-F1s (n=10) and sex/age matched control participants (n=41 for psychometrics; n=59 for eye-tracking) were recruited from the PE-NET study or extracted from the NeuroDevNet study databases. Participants completed a selected array of psychometric tests which assessed executive function, working memory, attention, inhibition, visuospatial processing, reading, and math skills. Eye-tracking studies included the prosaccade, antisaccade, and memory-guided tasks. Psychometric testing revealed an impairment in working memory among PE-F1s. Eye-tracking studies revealed numerous impairments among PE-F1s including additional saccades required to reach the target, poor endpoint accuracy, and slower reaction time. However, PE-F1s made faster saccades than controls, and fewer sequence errors in the memory-guided task. Our study provides a comprehensive assessment of cognitive function among PE-F1s. The development of PE may be seen as an early predictor of reduced cognitive function in children, specifically in working memory and oculomotor control. Future studies should extended to a larger study populations, and may be valuable for early studies of children born to pregnancies complicated by other disorders, such as gestational diabetes or intrauterine growth restriction.


Assuntos
Filho de Pais com Deficiência , Transtornos Cognitivos/etiologia , Deficiências do Desenvolvimento/etiologia , Pré-Eclâmpsia/fisiopatologia , Criança , Função Executiva/fisiologia , Movimentos Oculares/fisiologia , Feminino , Humanos , Inibição Psicológica , Masculino , Memória de Curto Prazo/fisiologia , Testes Neuropsicológicos , Gravidez , Psicometria , Desempenho Psicomotor/fisiologia
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