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bioRxiv · 10.1101/2025.06.02.657522

Purinergic receptor activation rectifies autism-associated endothelial dysfunction

Ouellette, J.·Warsi, S.·Romero, P.·Khare, P.·Naz, S.·Aubert-Tandon, L.·Pileggi, C.·Yandiev, S.·Freitas-Andrade, M.·Comin, C. H.·Harper, M.-E.·Manickam, D. S.·Dabertrand, F.·Saghatelyan, A.·Lacoste, B.
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Abstract

Early cerebrovascular alterations affect brain maturation by impacting trophic support and energy supply. Recent evidence in a 16p11.2 deletion mouse model of autism spectrum disorder (ASD) revealed brain endothelial abnormalities postnatally. Yet, the endothelial alterations eliciting these changes remain unknown. Isolation of brain endothelial cells (ECs) from 14-day old male 16p11.2-deficient and wild-type mice revealed that 16p11.2 deletion-induced endothelial dysfunction is linked to a bioenergetic failure, with reduced intracellular ATP. Intra- or extra-cellular ATP supplementation rescued the function of 16p11.2-deficient ECs in vitro via P2 purinergic receptor activation, specifically P2Y2 receptors. Activating P2Y2 receptors restored cerebrovascular reactivity in 16p11.2-deficient parenchymal arterioles ex vivo and rescued 16p11.2 deletion-associated mouse behaviors. Taken together, this study demonstrates that metabolic reprogramming of brain ECs via purinergic receptor engagement represents a possible therapeutic avenue for ASD.

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Ouellette, J., Warsi, S., Romero, P., Khare, P., Naz, S., Aubert-Tandon, L., Pileggi, C., Yandiev, S., Freitas-Andrade, M., Comin, C. H., Harper, M.-E., Manickam, D. S., Dabertrand, F., Saghatelyan, A., Lacoste, B.. 2025-06-03. Purinergic receptor activation rectifies autism-associated endothelial dysfunction. https://doi.org/10.1101/2025.06.02.657522

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