tPA-NMDAR Signaling Blockade Reduces the Incidence of Intracerebral Aneurysms

Estelle R. Louet, Martina Glavan, Cyrille Orset, Jerome Parcq, Daniel F. Hanley, Denis Vivien

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1005-1016
Number of pages12
JournalTranslational Stroke Research
Volume13
Issue number6
DOIs
StatePublished - Dec 2022

Keywords

  • Intracranial aneurysms
  • Preclinical rodent model
  • Subarachnoid hemorrhage
  • tPA

ASJC Scopus subject areas

  • General Neuroscience
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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