Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation

Author:

Globisch Maria A.1ORCID,Onyeogaziri Favour C.1ORCID,Jauhiainen Suvi1ORCID,Yau Anthony C. Y.1ORCID,Orsenigo Fabrizio2ORCID,Conze Lei L.1ORCID,Arce Maximiliano1ORCID,Corada Monica2ORCID,Smith Ross O.1ORCID,Rorsman Charlotte1,Sundell Veronica1,Fernando Dinesh3ORCID,Daniel Geoffrey3ORCID,Mattsson Oscar1,Savander Henri4,Wanders Alkwin5ORCID,Rezai Jahromi Behnam4ORCID,Laakso Aki4ORCID,Niemelä Mika4ORCID,Dejana Elisabetta12ORCID,Magnusson Peetra U.1ORCID

Affiliation:

1. 1Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

2. 2Vascular Biology Unit, IFOM ETS—The AIRC Institute of Molecular Oncology, Milan, Italy

3. 3Department of Biomaterials and Technology/Wood Science, Swedish University of Agricultural Sciences, Uppsala, Sweden

4. 4Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

5. 5Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark

Abstract

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 the transcriptome of mouse brain endothelial cells with an inducible endothelial-specific Ccm3 knock-out (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 with 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. 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 CCMs. This study supports the concept that antithrombotic therapy may be beneficial for patients with CCM.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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