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

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

  • Nat Commun. 2024 Sep 29;15(1):8430. doi: 10.1038/s41467-024-52654-2.
Martin Pedard 1 2,  Lucie Prevost # 1 2,  Camille Carpena # 3,  Brian Holleran # 4,  Laurence Desrues # 1 2,  Martine Dubois # 1 2,  Celeste Nicola 1 2,  Roxane Gruel 1 2,  David Godefroy 2 5,  Thomas Deffieux 6,  Mickael Tanter 6,  Carine Ali 7,  Richard Leduc 4,  Laurent Prézeau 3,  Pierrick Gandolfo 1 2,  Fabrice Morin 1 2,  Olivier Wurtz 1 2,  Thomas Bonnard 7,  Denis Vivien 7 8,  Hélène Castel 9 10
Affiliations

Affiliations

  • 1 Univ Rouen Normandie, Inserm, Normandie Univ, CBG UMR 1245, Rouen, France.
  • 2 Institute of Research and Innovation in Biomedicine (IRIB), Rouen, France.
  • 3 Institut de Génomique Fonctionnelle, Univ. Montpellier, CNRS, Inserm, Montpellier, France.
  • 4 Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
  • 5 Univ Rouen Normandie, Inserm, Normandie Univ, NorDiC UMR 1239, Rouen, France.
  • 6 Institute Physics for Medicine, Inserm U1273, CNRS UMR 8631, ESPCI Paris, Paris Sciences et Lettres PSL University, Paris, France.
  • 7 Normandie Université, UNICAEN, INSERM U1237, PhIND "Physiopathology and Imaging of Neurological Disorders", Institut Blood and Brain @ Caen-Normandie, GIP Cyceron, Caen, France.
  • 8 Centre Hospitalier Universitaire Caen, Department of Clinical Research, Caen, France.
  • 9 Univ Rouen Normandie, Inserm, Normandie Univ, CBG UMR 1245, Rouen, France. helene.castel@univ-rouen.fr.
  • 10 Institute of Research and Innovation in Biomedicine (IRIB), Rouen, France. helene.castel@univ-rouen.fr.
  • # Contributed equally.
PMID: 39341842 DOI: 10.1038/s41467-024-52654-2
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.

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