Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation

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MARC

Fältnamn	Indikatorer	Metadata
000		06843naa a2200673 4500
001		oai:DiVA.org:uu-489038
003		SwePub
008		221125s2022 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
009		oai:slubar.slu.se:118492
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4890382 URI
024	7	a https://doi.org/10.1182/blood.20210153502 DOI
024	7	a https://res.slu.se/id/publ/1184922 URI
040		a (SwePub)uud (SwePub)slu
041		a engb swe
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Globisch, Maria A.u Uppsala universitet,Vaskulärbiologi,Magnusson4 aut0 (Swepub:uu)margl506
245	1 0	a Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation
264	1	b American Society of Hematology,c 2022
338		a electronic2 rdacarrier
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Hematologi0 (SwePub)302022 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Hematology0 (SwePub)302022 hsv//eng
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Neurologi0 (SwePub)302072 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Neurology0 (SwePub)302072 hsv//eng
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Cell- och molekylärbiologi0 (SwePub)301082 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Cell and Molecular Biology0 (SwePub)301082 hsv//eng
653		a Immunologi
653		a Immunology
700	1	a Onyeogaziri, Favour C.u Uppsala universitet,Vaskulärbiologi,Magnusson4 aut0 (Swepub:uu)favon830
700	1	a Jauhiainen, Suviu Uppsala universitet,Vaskulärbiologi,Dejana4 aut0 (Swepub:uu)suvja782
700	1	a Yau, Anthony C. Y.u Uppsala universitet,Vaskulärbiologi,Dejana4 aut0 (Swepub:uu)antya284
700	1	a Orsenigo, Fabriziou Vascular Biology Unit, IFOM ETS—The AIRC Institute of Molecular Oncology, Milan, Italy4 aut
700	1	a Conze, Lei L.u Uppsala universitet,Vaskulärbiologi,Dejana4 aut0 (Swepub:uu)leliu102
700	1	a Arce, Maximilianou Uppsala universitet,Vaskulärbiologi,Dejana4 aut0 (Swepub:uu)maxar829
700	1	a Corada, Monicau Vascular Biology Unit, IFOM ETS—The AIRC Institute of Molecular Oncology, Milan, Italy4 aut
700	1	a Smith, Ross O.u Uppsala universitet,Vaskulärbiologi,Dejana4 aut0 (Swepub:uu)rossm781
700	1	a Rorsman, Charlotteu Uppsala universitet,Vaskulärbiologi,Dejana4 aut0 (Swepub:uu)charrors
700	1	a Sundell, Veronicau Uppsala universitet,Vaskulärbiologi,Dejana4 aut0 (Swepub:uu)versu224
700	1	a Fernando, Dineshu 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, Sweden4 aut0 (Swepub:slu)50319
700	1	a Daniel, Geoffreyu 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, Sweden4 aut0 (Swepub:slu)47230
700	1	a Mattsson, Oscaru Uppsala universitet,Vaskulärbiologi,Dejana4 aut
700	1	a Savander, Henriu Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland4 aut
700	1	a Wanders, Alkwinu Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark4 aut
700	1	a Rezai Jahromi, Behnamu Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland4 aut
700	1	a Laakso, Akiu Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland4 aut
700	1	a Niemelä, Mikau Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland4 aut
700	1	a Dejana, Elisabettau Uppsala universitet,Vaskulärbiologi,Vascular Biology Unit, IFOM ETS—The AIRC Institute of Molecular Oncology, Milan, Italy,Dejana4 aut0 (Swepub:uu)elide443
700	1	a Magnusson, Peetra U.u Uppsala universitet,Vaskulärbiologi,Magnusson4 aut0 (Swepub:uu)petrmagn
710	2	a Uppsala universitetb Vaskulärbiologi4 org
710	2	a Sveriges lantbruksuniversitet
773	0	t Bloodd : American Society of Hematologyg 140:20, s. 2154-2169q 140:20<2154-2169x 0006-4971x 1528-0020
856	4	u https://doi.org/10.1182/blood.2021015350y Fulltext
856	4	u https://uu.diva-portal.org/smash/get/diva2:1713623/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
856	4	u https://pub.epsilon.slu.se/id/eprint/29924/contentsx primaryx Raw objectx freey FULLTEXT
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-489038
856	4 8	u https://doi.org/10.1182/blood.2021015350
856	4 8	u https://res.slu.se/id/publ/118492

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Hematology

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