Neurovascular connectedness and blood-brain interfaces integrity under fetal growth restriction: between resilience and vulnerability

Abstract Background Fetal growth restriction is an important public health concern caused by placental insufficiency or malnutrition. It results in a reduced brain weight and an increased risk of neurodevelopmental disorders. The maturation of neuronal networks critically depends on adequate CNS homeostasis, which is controlled by the blood-brain and blood-CSF interfaces, i.e. the cerebral vasculature and the choroid plexuses. In this paper, we investigate the impact of fetal growth restriction induced by protein deficiency during gestation on the postnatal development of neurovascular networks and the integrity of blood-brain interfaces under normal conditions and after systemic stresses. Methods We used snRNA-Seq and a Supernova-based approach coupled with three-dimensional analyses of pyramidal cell dendritic arborization and associated vasculature in rats, to study the development of cortical neuronal and vascular networks and their connectedness. Permeability to sucrose and pleocytosis measurements has been performed to assess the integrityof blood-brain interfaces in vivo in different pathological settings. Results We show that the development of cortical neuronal and vascular networks and their connectedness are resilient to protein deprivation. Yet, these networks exhibit long-term characteristics indicative of impacted fetal programming. We provide quantitative data showing in vivo the fragility of both the blood-CSF and blood-brain barriers in developing animals subjected to fetal growth restriction, and an inability of these interfaces to cope with additional systemic inflammatory stresses during the early postnatal period. The extent of this latter impairment varies between individuals. Conclusions Protein deficiency that induces fetal growth restriction spares the structures responsible for higher cognitive functions. However, it does induce subtle yet potentially deleterious changes in neurovascular interactions. The altered functional integrity of the brain barriers caused by protein deprivation is a neglected but important consequence of fetal growth restriction. It represents a risk for an unstable cerebral environment affecting postnatal development, and for cerebral toxicity induced by environmental xenobiotics. Inter-individual variability in brain barriers fragility is a previously undescribed factor that needs to be considered when determining the degree to which infants who experienced fetal growth restriction are vulnerable to the appearance of central adverse outcomes following systemic stresses.