Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice

Cerebral cavernous malformations (CCMs) are common brain vascular dysplasias that are prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here, we show that central nervous system hemorrhage in CCMs is as...

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Vydané v:	Blood Ročník 133; číslo 3; s. 193
Hlavní autori:	Lopez-Ramirez, Miguel Alejandro, Pham, Angela, Girard, Romuald, Wyseure, Tine, Hale, Preston, Yamashita, Atsuki, Koskimäki, Janne, Polster, Sean, Saadat, Laleh, Romero, Ignacio A, Esmon, Charles T, Lagarrigue, Frederic, Awad, Issam A, Mosnier, Laurent O, Ginsberg, Mark H
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 17.01.2019
Predmet:	Adult Animals Anticoagulants - metabolism Apoptosis Regulatory Proteins - physiology Blood Coagulation Case-Control Studies Cerebral Hemorrhage - blood Cerebral Hemorrhage - diagnosis Cerebral Hemorrhage - etiology Endothelial Protein C Receptor - metabolism Endothelium, Vascular - metabolism Endothelium, Vascular - pathology Hemangioma, Cavernous, Central Nervous System - complications Hemangioma, Cavernous, Central Nervous System - metabolism Hemangioma, Cavernous, Central Nervous System - physiopathology Humans KRIT1 Protein - physiology Membrane Proteins - physiology Mice Mice, Knockout Protein C - metabolism Proto-Oncogene Proteins - physiology Signal Transduction Thrombomodulin - blood Young Adult
ISSN:	1528-0020, 1528-0020
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Shrnutí:	Cerebral cavernous malformations (CCMs) are common brain vascular dysplasias that are prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here, we show that central nervous system hemorrhage in CCMs is associated with locally elevated expression of the anticoagulant endothelial receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR). TM levels are increased in human CCM lesions, as well as in the plasma of patients with CCMs. In mice, endothelial-specific genetic inactivation of ( ) or ( ), which cause CCM formation, results in increased levels of vascular TM and EPCR, as well as in enhanced generation of activated protein C (APC) on endothelial cells. Increased TM expression is due to upregulation of transcription factors KLF2 and KLF4 consequent to the loss of or Increased TM expression contributes to CCM hemorrhage, because genetic inactivation of 1 or 2 copies of the gene decreases brain hemorrhage in mice. Moreover, administration of blocking antibodies against TM and EPCR significantly reduced CCM hemorrhage in mice. Thus, a local increase in the endothelial cofactors that generate anticoagulant APC can contribute to bleeding in CCMs, and plasma soluble TM may represent a biomarker for hemorrhagic risk in CCMs.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1528-0020 1528-0020
DOI:	10.1182/blood-2018-06-856062