Maternal immune activation leads to defective brain–blood vessels and intracerebral hemorrhages in male offspring. (31st October 2022)

• Record Type: Journal Article
• Authors: Rasile, Marco; Lauranzano, Eliana; Faggiani, Elisa; Ravanelli, Margherita M; Colombo, Federico S; Mirabella, Filippo; Corradini, Irene; Malosio, Maria L; Borreca, Antonella; Focchi, Elisa; Pozzi, Davide; Giorgino, Toni; Barajon, Isabella; Matteoli, Michela
• Is Part Of: EMBO journal. Volume 41:Number 23(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-10-31
• Subjects: CD146 -- intracerebral hemorrhages -- MIA -- NVU -- sex dimorphism; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2022111192
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Intracerebral hemorrhages are recognized risk factors for neurodevelopmental disorders and represent early biomarkers for cognitive dysfunction and mental disability, but the pathways leading to their occurrence are not well defined. We report that a single intrauterine exposure of the immunostimulant Poly I:C to pregnant mice at gestational day 9, which models a prenatal viral infection and the consequent maternal immune activation, induces the defective formation of brain vessels and causes intracerebral hemorrhagic events, specifically in male offspring. We demonstrate that maternal immune activation promotes the production of the TGF‐β1 active form and the consequent enhancement of pSMAD1‐5 in males' brain endothelial cells. TGF‐β1, in combination with IL‐1β, reduces the endothelial expression of CD146 and claudin‐5, alters the endothelium–pericyte interplay resulting in low pericyte coverage, and increases hemorrhagic events in the adult offspring. By showing that exposure to Poly I:C at the beginning of fetal cerebral angiogenesis results in sex‐specific alterations of brain vessels, we provide a mechanistic framework for the association between intragravidic infections and anomalies of the neural vasculature, which may contribute to neuropsychiatric disorders. Synopsis: A mouse model of viral infection during pregnancy shows that maternal immune activation results in male‐specific defects in the formation of brain vasculature in the offspring leading to fragile and hemorrhage‐prone blood vessels. A single intrauterine exposure to Poly I:C in pregnant mice leads to disruption of endothelial cell–pericyte interplay in the brain–blood vessels of the offspring. Breakdown of the neurovascular unit results in hemorrhage‐prone vessels. Maternal immune activation leads to the induction of TGF‐β and reduced endothelial expression of CD146 selectively in male mice. Male brain–blood vessels show a reduced number of pericytes and concomitant disruption of the tight junction protein CLND5. Abstract : Viral infection during mouse pregnancy results in sex‐specific impairment of brain vasculature formation and function.