The urotensin II receptor triggers an early meningeal response and a delayed macrophage-dependent vasospasm after subarachnoid hemorrhage in male mice

Martin Pedard, Lucie Prevost, Camille Carpena, Brian Holleran, Laurence Desrues, Martine Dubois, Celeste Nicola, Roxane Gruel, David Godefroy, Thomas Deffieux, Mickael Tanter, Carine Ali, Richard Leduc, Laurent Prézeau, Pierrick Gandolfo, Fabrice Morin, Olivier Wurtz, Thomas Bonnard, Denis Vivien and Hélène Castel ()
Additional contact information
Martin Pedard: CBG UMR 1245
Lucie Prevost: CBG UMR 1245
Camille Carpena: Inserm
Brian Holleran: Université de Sherbrooke
Laurence Desrues: CBG UMR 1245
Martine Dubois: CBG UMR 1245
Celeste Nicola: CBG UMR 1245
Roxane Gruel: CBG UMR 1245
David Godefroy: Institute of Research and Innovation in Biomedicine (IRIB)
Thomas Deffieux: Paris Sciences et Lettres PSL University
Mickael Tanter: Paris Sciences et Lettres PSL University
Carine Ali: GIP Cyceron
Richard Leduc: Université de Sherbrooke
Laurent Prézeau: Inserm
Pierrick Gandolfo: CBG UMR 1245
Fabrice Morin: CBG UMR 1245
Olivier Wurtz: CBG UMR 1245
Thomas Bonnard: GIP Cyceron
Denis Vivien: GIP Cyceron
Hélène Castel: CBG UMR 1245

Nature Communications, 2024, vol. 15, issue 1, 1-27

Abstract: Abstract Subarachnoid hemorrhage (SAH) can be associated with neurological deficits and has profound consequences for mortality and morbidity. Cerebral vasospasm (CVS) and delayed cerebral ischemia affect neurological outcomes in SAH patients, but their mechanisms are not fully understood, and effective treatments are limited. Here, we report that urotensin II receptor UT plays a pivotal role in both early events and delayed mechanisms following SAH in male mice. Few days post-SAH, UT expression is triggered by blood or hemoglobin in the leptomeningeal compartment. UT contributes to perimeningeal glia limitans astrocyte reactivity, microvascular alterations and neuroinflammation independent of CNS-associated macrophages (CAMs). Later, CAM-dependent vascular inflammation and subsequent CVS develop, leading to cognitive dysfunction. In an SAH model using humanized UTh+/h+ male mice, we show that post-SAH CVS and behavioral deficits, mediated by UT through Gq/PLC/Ca2+ signaling, are prevented by UT antagonists. These results highlight the potential of targeting UT pathways to reduce early meningeal response and delayed cerebral ischemia in SAH patients.

Date: 2024
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DOI: 10.1038/s41467-024-52654-2

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