Sex-Specific Neurovascular and Cognitive Deficits in Offspring of Preeclampsia

Escudero, C.; Troncoso, F.; Sandoval, H.; Escudero-Guevara, E. A.; Nualart, F.; Ramirez, E.; SANDANA, P. R.; Ek, C. J.; Herrock, O. T.; Merceron, D.; Ardiles, A. O.; Vatish, M.; Acurio, J.

doi:10.1101/2025.08.21.671659

bioRxiv · 10.1101/2025.08.21.671659

Sex-Specific Neurovascular and Cognitive Deficits in Offspring of Preeclampsia

Escudero, C.·Troncoso, F.·Sandoval, H.·Escudero-Guevara, E. A.·Nualart, F.·Ramirez, E.·SANDANA, P. R.·Ek, C. J.·Herrock, O. T.·Merceron, D.·Ardiles, A. O.·Vatish, M.·Acurio, J.

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Abstract

BackgroundOffspring of preeclampsia may develop long-term neurovascular and cognitive impairments, but the underlying mechanisms remain unclear. We investigate sex-specific alterations in brain vascular function and cognition in a murine model of preeclampsia induced by the nitric oxide synthase inhibitor L-NAME. MethodsPregnant mice received L-NAME (gestational day 7 to 19). Offspring were assessed at postnatal day 5 (P5) and in adulthood (4-5 months). Brain vascular development, angiogenesis, perfusion, cold-induced vasoconstriction, and blood-brain barrier (BBB) integrity were assessed in vivo and ex vivo. Offsprings serum was applied to brain endothelial cell cultures to evaluate endothelial activation and barrier function. Adult cognitive performance was evaluated through behavioral tests and hippocampal long-term potentiation (LTP) recordings. ResultsL-NAME offspring (P5) exhibited reduced brain vascular density, decreased tip cell formation, and impaired cold-induced vasoconstriction, most prominently in males. BBB integrity was compromised, with increased permeability and reduced expression of tight junction proteins (claudin-5, ZO-1), again more pronounced in males. Serum from L-NAME offspring induced endothelial activation and barrier dysfunction in vitro. These effects were accompanied by increased brain and systemic levels of hypoxia markers and proinflammatory cytokines (IL-6, TNF-). Adult L-NAME offspring showed cognitive deficits in recognition and spatial memory tasks, with female offspring displaying more pronounced impairments. These behavioral findings paralleled a reduced magnitude and impaired stabilization of hippocampal LTP in females. ConclusionsPrenatal exposure to a preeclampsia-like environment induces persistent, sex-specific neurovascular and cognitive deficits in offspring. These findings underscore the need for long-term neurological follow-up in children born to preeclamptic pregnancies.

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Escudero, C., Troncoso, F., Sandoval, H., Escudero-Guevara, E. A., Nualart, F., Ramirez, E., SANDANA, P. R., Ek, C. J., Herrock, O. T., Merceron, D., Ardiles, A. O., Vatish, M., Acurio, J.. 2025-08-26. Sex-Specific Neurovascular and Cognitive Deficits in Offspring of Preeclampsia. https://doi.org/10.1101/2025.08.21.671659

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