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Immunothrombosis an...
Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation
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- Globisch, Maria A. (author)
- Uppsala universitet,Vaskulärbiologi,Magnusson
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- Onyeogaziri, Favour C. (author)
- Uppsala universitet,Vaskulärbiologi,Magnusson
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- Jauhiainen, Suvi (author)
- Uppsala universitet,Vaskulärbiologi,Dejana
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- Yau, Anthony C. Y. (author)
- Uppsala universitet,Vaskulärbiologi,Dejana
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- Orsenigo, Fabrizio (author)
- Vascular Biology Unit, IFOM ETS—The AIRC Institute of Molecular Oncology, Milan, Italy
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- Conze, Lei L. (author)
- Uppsala universitet,Vaskulärbiologi,Dejana
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- Arce, Maximiliano (author)
- Uppsala universitet,Vaskulärbiologi,Dejana
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- Corada, Monica (author)
- Vascular Biology Unit, IFOM ETS—The AIRC Institute of Molecular Oncology, Milan, Italy
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- Smith, Ross O. (author)
- Uppsala universitet,Vaskulärbiologi,Dejana
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- Rorsman, Charlotte (author)
- Uppsala universitet,Vaskulärbiologi,Dejana
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- Sundell, Veronica (author)
- Uppsala universitet,Vaskulärbiologi,Dejana
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- Fernando, Dinesh (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Skogens biomaterial och teknologi,Department of Forest Biomaterials and Technology,Department of Biomaterials and Technology/Wood Science, Swedish University of Agricultural Sciences, Uppsala, Sweden
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- Daniel, Geoffrey (author)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Skogens biomaterial och teknologi,Department of Forest Biomaterials and Technology,Department of Biomaterials and Technology/Wood Science, Swedish University of Agricultural Sciences, Uppsala, Sweden
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- Mattsson, Oscar (author)
- Uppsala universitet,Vaskulärbiologi,Dejana
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- Savander, Henri (author)
- Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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- Wanders, Alkwin (author)
- Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark
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- Rezai Jahromi, Behnam (author)
- Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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- Laakso, Aki (author)
- Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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- Niemelä, Mika (author)
- Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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- Dejana, Elisabetta (author)
- Uppsala universitet,Vaskulärbiologi,Vascular Biology Unit, IFOM ETS—The AIRC Institute of Molecular Oncology, Milan, Italy,Dejana
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- Magnusson, Peetra U. (author)
- Uppsala universitet,Vaskulärbiologi,Magnusson
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(creator_code:org_t)
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- American Society of Hematology, 2022
- 2022
- English.
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 140:20, s. 2154-2169
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://res.slu.se/i...
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- Immunologi
- Immunology
Publication and Content Type
- ref (subject category)
- art (subject category)
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Globisch, Maria ...
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Onyeogaziri, Fav ...
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Jauhiainen, Suvi
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Yau, Anthony C. ...
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Orsenigo, Fabriz ...
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Conze, Lei L.
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Arce, Maximilian ...
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Corada, Monica
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Smith, Ross O.
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Rorsman, Charlot ...
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Sundell, Veronic ...
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Fernando, Dinesh
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Daniel, Geoffrey
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Mattsson, Oscar
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Savander, Henri
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Wanders, Alkwin
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Rezai Jahromi, B ...
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Laakso, Aki
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Niemelä, Mika
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Dejana, Elisabet ...
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Magnusson, Peetr ...
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- MEDICAL AND HEALTH SCIENCES
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and Clinical Medicin ...
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and Hematology
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Neurology
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MEDICAL AND HEAL ...
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Blood
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Uppsala University
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Swedish University of Agricultural Sciences