Neurological consequences of neurovascular unit and brain vasculature damages: potential risks for pregnancy infections and COVID‐19‐babies

Abstract

Intragravidic and perinatal infections, acting through either direct viral effect or immune-mediated responses, are recognized causes of liability for neurodevelopmental disorders in the progeny. The large amounts of epidemiological data and the wealth of information deriving from animal models of gestational infections have contributed to delineate, in the last years, possible underpinning mechanisms for this phenomenon, including defects in neuronal migration, impaired spine and synaptic development, and altered activation of microglia. Recently, dysfunctions of the neurovascular unit and anomalies of the brain vasculature have unexpectedly emerged as potential causes at the origin of behavioral abnormalities and psychiatric disorders consequent to prenatal and perinatal infections. This review aims to discuss the up-to-date literature evidence pointing to the neurovascular unit and brain vasculature damages as the etiological mechanisms in neurodevelopmental syndromes. We focus on the inflammatory events consequent to intragravidic viral infections as well as on the direct viral effects as the potential primary triggers. These authors hope that a timely review of the literature will help to envision promising research directions, also relevant for the present and future COVID-19 longitudinal studies.

Maternal immune activation leads to defective brain–blood vessels and intracerebral hemorrhages in male offspring

“…Although anomalies in blood vessel formation are known to result in long‐lasting consequences and impairments in brain maturation, the origins of these anomalies are still not fully clarified. We have previously hypothesized that inflammatory events consequent to viral infections during the gestational period could act as potential primary triggers for brain vasculature damage (Rasile et al , 2021 ). In this study, we provide a direct demonstration that this is the case.…”

“…Several concomitant events are thought to be the basis of the increased susceptibility to neurodevelopmental diseases upon maternal immune activation (Haddad et al , 2020 ; Han et al , 2021 ). Interestingly, however, accumulating evidence suggests that anomalies of the vasculature are involved in the pathogenesis of neurodevelopmental disorders (Kealy et al , 2020 ; Rasile et al , 2021 ). We demonstrate here that MIA, applied in a developmental time window corresponding to angiogenesis, BBB formation, and neurogenesis (Vasudevan et al , 2008 ), results in altered blood vessel formation and BBB maturation.…”

“…The occurrence of brain bleedings has been previously reported to associate with pericyte paucity, which causes intraventricular hemorrhages of the germinal matrix (GH‐IVH) in prematurely born babies (Braun et al , 2007). Moreover, the occurrence of hemorrhagic events, together with low levels of CD146, has been linked to the occurrence of neuropsychiatric diseases (Greene et al , 2019; Rasile et al , 2021). Perinatal brain hemorrhages are a risk factor for schizophrenia (Rosanoff et al , 1934; Torrey et al , 1975) and indeed the injection in mouse fetuses of the pro‐hemorrhagic agent lysophosphatidic acid (LPA) induces schizophrenic‐like behaviors in experimental animals (Mirendil et al , 2015).…”

Cerebral Malformations Related to Coronavirus Disease 2019 during Pregnancy

“…[38][39][40][41][42][43][44][45][46] In fact, in fetal brain development, microglia regulates important processes such as neuronal differentiation, neural circuit formation, and an inflammatory state may interfere with microglia and neuronal migration leading to atypical brain structure and function. 47,48 During pregnancy, there is a modified balance of cytokines formed by T-helper (TH) lymphocytes: there is a downregulation of proinflammatory TH1 cells with a consequent reduction of gamma-interferon, interleukin (IL)-1α, IL-1β, IL-6, and IL-12 levels. On the contrary, there is a higher production of TH2 ILs (IL-4, IL-10, IL-13) and transforming growth factor-beta, leading to increased maternal susceptibility to viral pathogens such as SARS-CoV-2.…”

Systemic Inflammation and Astrocyte Reactivity in the Neuropsychiatric Sequelae of COVID-19: Focus on Autism Spectrum Disorders

“…Despite the lack of evidence, a link between maternal SARS-CoV-2 infection and ASD can be speculated. It is well known that the perinatal environment markedly affects brain development and function, and, for this reason, some of the cellular and molecular alterations caused by SARS-CoV-2 could hypothetically promote ASD ( Figure 1 ) (Steinman, 2020a ; Rasile et al, 2021 ). Above all, the activation of the maternal immune system with the subsequent exposure of the foetus to high levels of cytokines, chemokines, and other mediators of inflammation through maternal serum, placenta, and amniotic fluid may impact on the brain (Knuesel et al, 2014 ).…”