Skip to main content
Research article - Peer-reviewed, 2022

Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation

Globisch, Maria A.; Onyeogaziri, Favour C.; Jauhiainen, Suvi; Yau, Anthony; Orsenigo, Fabrizio; Conze, Lei L.; Arce, Maximiliano; Corada, Monica; Smith, Ross; Rorsman, Charlotte; Sundell, Veronica; Fernando, Dinesh; Daniel, Geoffrey; Mattsson, Oscar; Savander, Henri; Wanders, Alkwin; Jahromi, Behnam Rezai; Laakso, Aki; Niemelä, Mika; Dejana, Elisabetta;
Show more authors

Abstract

Cerebral cavernous malformation (CCM) is a neurovascular disease that results in various neurological symptoms. Thrombi have been reported in surgically resected CCM patient biopsies; but the molecular signatures of these thrombi remain elusive. Here, we investigated the kinetics of thrombi formation in CCM and how thrombi affect the vasculature and contribute to cerebral hypoxia. We used RNA-sequencing to investigate mouse brain endothelial cells with specific Ccm3 gene deletion (Ccm3-iECKO). We found that Ccm3 deficient brain endothelial cells had a higher expression of genes related to the coagulation cascade and hypoxia when compared to wild-type brain endothelial cells. Immunofluorescent assays identified key molecular signatures of thrombi such as fibrin, von Willebrand factor, and activated platelets in Ccm3-iECKO mice and human CCM biopsies. Notably, we identified polyhedrocytes in Ccm3-iECKO mice and human CCM biopsies and report it for the first time. We also found that the parenchyma surrounding CCM lesions is hypoxic and that more thrombi correlate with higher levels of hypoxia. Lastly, we created an in vitro model to study CCM pathology and found that human brain endothelial cells deficient for CCM3, expressed elevated levels of plasminogen activator inhibitor-1 and had a redistribution of von Willebrand factor. With transcriptomics, comprehensive imaging, and an in vitro CCM preclinical model this study provides experimental evidence that genes and proteins related to the coagulation cascade affect the brain vasculature and promote neurological side effects such as hypoxia in CCM. This study supports the concept that antithrombotic therapy may be beneficial for patients with CCM.

Keywords

Free Research Articles,; Thrombosis and Hemostasis; Vascular Biology

Published in

Blood
2022, volume: 140, number: 20, pages: 2154–2169

Authors' information

Globisch, Maria A.
Uppsala University
Onyeogaziri, Favour C.
Uppsala University
Jauhiainen, Suvi
Uppsala University
Yau, Anthony
Uppsala University
Orsenigo, Fabrizio
IFOM - FIRC Institute of Molecular Oncology
Conze, Lei L.
Uppsala University
Arce, Maximiliano
Uppsala University
Corada, Monica
IFOM - FIRC Institute of Molecular Oncology
Smith, Ross
Uppsala University
Rorsman, Charlotte
Uppsala University
Sundell, Veronica
Uppsala University
Swedish University of Agricultural Sciences, Department of Forest Biomaterials and Technology
Swedish University of Agricultural Sciences, Department of Forest Biomaterials and Technology
Mattsson, Oscar
Uppsala University
Savander, Henri
University of Helsinki
Wanders, Alkwin
Aalborg university hospital
Jahromi, Behnam Rezai
University of Helsinki
Laakso, Aki
University of Helsinki
Niemelä, Mika
University of Helsinki
Dejana, Elisabetta
Uppsala University
Show more authors

UKÄ Subject classification

Cell and Molecular Biology

Publication Identifiers

DOI: https://doi.org/10.1182/blood.2021015350

URI (permanent link to this page)

https://res.slu.se/id/publ/118492