tPA-NMDAR Signaling Blockade Reduces the Incidence of Intracerebral Aneurysms.
Intracranial aneurysms
Preclinical rodent model
Subarachnoid hemorrhage
tPA
Journal
Translational stroke research
ISSN: 1868-601X
Titre abrégé: Transl Stroke Res
Pays: United States
ID NLM: 101517297
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
08
10
2021
accepted:
04
03
2022
revised:
03
03
2022
pubmed:
22
3
2022
medline:
1
11
2022
entrez:
21
3
2022
Statut:
ppublish
Résumé
Intracranial aneurysms (IAs) are pathological dilatations affecting cerebral arteries, and their ruptures lead to devasting intracranial hemorrhages. Although the mechanisms underlying the IA formation and rupture are still unclear, some factors have been identified as critical in the control of the vascular remodeling pathways associated with aneurysms. In a preclinical model, we have previously proposed the implication of the vascular serine protease, the tissue-type plasminogen activator (tPA), as one of the key players in this pathology. Here, we provide insights into the mechanism by which tPA is implicated in the formation and rupture of aneurysms. This was addressed using a murine model of IAs combined with (i) hydrodynamic transfections of various tPA mutants based on the potential implications of the different tPA domains in this pathophysiology and (ii) a pharmacological approach using a monoclonal antibody targeting tPA-dependent NMDA receptor (NMDAR) signaling and in vivo magnetic resonance brain imaging (MRI). Our results show that the endovascular tPA-NMDAR axis is implicated in IA formation and possibly their rupture. Accordingly, the use of a monoclonal antibody designed to block tPA-dependent endothelial NMDAR signaling (Glunomab®) decreases the rate of intracranial aneurysm formation and their rupture. The present study gives new insights into the IA pathophysiology by demonstrating the implication of the tPA-dependent endothelial NMDAR signaling. In addition, the present data proposes that a monoclonal antibody injected intravenously to target this process, i.e., Glunomab® could be a useful therapeutic candidate for this devastating disease.
Identifiants
pubmed: 35307812
doi: 10.1007/s12975-022-01004-9
pii: 10.1007/s12975-022-01004-9
doi:
Substances chimiques
Tissue Plasminogen Activator
EC 3.4.21.68
Receptors, N-Methyl-D-Aspartate
0
N-Methylaspartate
6384-92-5
Antibodies, Monoclonal
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1005-1016Subventions
Organisme : Marie Curie
ID : 813294
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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