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    Oral Communication

    Vascular Biology

    Mechanisms Regulating Vessel Wall Function and Integrity

    OC 10.3 - Platelets mediate intracranial aneurysm formation and rupture in mice

    Saturday, June 24, 2023
    13:30 – 13:45 ET
    Room: 515
    Session Available As: On-Demand

      Presenting Author(s)

    • Clémence MAUPU

      Phd Student
      INSERM
      PARIS, Ile-de-France, France

      • Co-Author(s)

    • HL

      Héloïse Lebas, PhD

      Post-doc
      INSERM U1148, Université Paris Cité
      Paris, Ile-de-France, France

    • JS

      Jonas SALFATI

      technician
      INSERM
      PARIS, Ile-de-France, France

    • AB

      Alexandre Boutigny

      Dr
      INSERM
      PARIS, Ile-de-France, France

    • Caterina Casari, PhD (she/her/hers)

      Principal Investigator
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay
      PARIS, Ile-de-France, France

    • CF

      Craig Fletcher

      DR
      Department of Pathology and Laboratory Medicine
      Chapel Hill, New York, United States

    • jW

      jerry Ware

      Dr
      Physiology and Biophysics, University of Arkansas for Medical Sciences
      Little Rock, Arizona, United States

    • PC

      Pamela Conley

      DR
      Portola Pharmaceuticals, Inc.
      San fransisco, California, United States

    • PM

      Pierre Mangin

      Research Director
      Université de Strasbourg, INSERM, EFS Grand Est, BPPS UMR-S1255, FMTS, F-67065 Strasbourg, France
      Strasbourg, Alsace, France

    • BN

      Bernhard Nieswandt

      Professor
      Institute of Experimental Biomedicine - Chair I, University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Biomaging, University of Würzburg, Germany
      Würzburg, Bayern, Germany

    • SL

      Stéphane Loyau

      IE
      INSERM UMRS-1148
      PARIS, Ile-de-France, France

    • PB

      Philippe Bonnin

      Dr
      Service de physiopathologie clinique exploration fonctionnelles, AP-HP, hôpital Lariboisière
      PARIS, Ile-de-France, France

    • VA

      Véronique AROCAS

      Dr.
      Inserm U1148
      Paris, Ile-de-France, France

    • Martine JANDROT-PERRUS, MD., PhD. (she/her/hers)

      Emeritus Professor
      INSERM
      Paris, Ile-de-France, France

    • MB

      Marie-Christine BOUTON

      Dr.
      Inserm U1148
      Paris, Ile-de-France, France

    • YB

      Yacine Boulaftali, PhD

      Dr
      Unité INSERM U1148, Université Paris Cité
      Paris, Ile-de-France, France

    Background: Intracranial aneurysms (IA) are local abnormal dilatations of cerebral arteries due to a damaged vessel wall. Loss of vascular integrity (e.g elastin degradation), acute inflammation and the presence of an intrasaccular thrombus are the three main features of IA. Beyond their role in forming clots, activated platelets support leukocyte recruitment and safeguard the vasculature in inflammatory situations.

    Aims: To study the role of platelets in IA formation and rupture.

    Methods: IA was induced in mice with a model combining hypertension, elastin degradation and blood flow disruption in the circle of Willis. IA formation and rupture were monitored with transcranial Doppler, magnetic resonance imaging and quantified by histology.

    Results: To determine the mechanisms governing platelet interaction with the aneurysmal vessel wall, we used mice deficient in the von Willebrand factor (vWF) platelet receptor, GPIbα. Aneurysm formation was significantly decreased in both GPIbα and VWF deficient mice. Similarly, mice deficient for the platelet main fibrinogen receptor, integrin beta3, were also protected from IA formation. Mice deficient in the ADP receptor, P2Y12; and the collagen receptor, GPVI were protected from IA rupture while, thrombin receptor deficient mice (Par4-/-) displayed a significant increase in the incidence of IA rupture. To investigate the chemoattractant role of platelets in the pathogenesis of IA, we subjected mice deficient in the secreted platelet chemokine, CXCL4, to our model. Aneurysm rupture was significantly higher in CXCL4 deficient mice.

    Conclusion(s): Overall, our data show that platelet/vessel adhesion and aggregation contribute to IA formation. In this model, platelet agonist receptors for collagen and thrombin differentially contribute to the aneurysm rupture while the platelet chemokine, CXCL4, plays a protective role in IA rupture. Further studies are required to better characterize the role of platelets in the vascular inflammation and remodeling during IA.

    Learning Objectives:

    • upon completion, participant will be able to distinguish the different platelets receptors that interact with the course of intracranial aneurysm pathology (Formation and rupture rate, immune cell recruitment etc...)
    • Upon completion, participants will be able to outline the features of intracranial aneurysm : elastin degradation, remodelling of the vascular wall, immune cell recruitement...
    • Upon completion, participants will learn about a murine model of intracranial aneurysm.