Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican.

Autor:	Hong CC; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA., Tang AT; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA., Detter MR; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC., Choi JP; Centenary Institute, Sydney Medical School, University of Sydney, Sydney, Australia., Wang R; Department of Pharmacology, School of Basic Medical Sciences, Tianjian Medical University, Tianjin, China., Yang X; Department of Pharmacology, School of Basic Medical Sciences, Tianjian Medical University, Tianjin, China., Guerrero AA; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA., Wittig CF; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA., Hobson N; Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, IL., Girard R; Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, IL., Lightle R; Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, IL., Moore T; Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, IL., Shenkar R; Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, IL., Polster SP; Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, IL., Goddard LM; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA., Ren AA; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA., Leu NA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA., Sterling S; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA., Yang J; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA., Li L; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA., Chen M; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA., Mericko-Ishizuka P; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA., Dow LE; Department of Medicine, Weill-Cornell Medicine, New York, NY., Watanabe H; Institute for Molecular Science of Medicine, Aichi Medical University, Aichi, Japan., Schwaninger M; Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lubeck, Lubeck, Germany., Min W; Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT., Marchuk DA; Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC., Zheng X; Centenary Institute, Sydney Medical School, University of Sydney, Sydney, Australia.; Department of Pharmacology, School of Basic Medical Sciences, Tianjian Medical University, Tianjin, China., Awad IA; Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, IL., Kahn ML; Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2020 Oct 05; Vol. 217 (10).
DOI:	10.1084/jem.20200140
Abstrakt:	Cerebral cavernous malformations (CCMs) form following loss of the CCM protein complex in brain endothelial cells due to increased endothelial MEKK3 signaling and KLF2/4 transcription factor expression, but the downstream events that drive lesion formation remain undefined. Recent studies have revealed that CCM lesions expand by incorporating neighboring wild-type endothelial cells, indicative of a cell nonautonomous mechanism. Here we find that endothelial loss of ADAMTS5 reduced CCM formation in the neonatal mouse model. Conversely, endothelial gain of ADAMTS5 conferred early lesion genesis in the absence of increased KLF2/4 expression and synergized with KRIT1 loss of function to create large malformations. Lowering versican expression reduced CCM burden, indicating that versican is the relevant ADAMTS5 substrate and that lesion formation requires proteolysis but not loss of this extracellular matrix protein. These findings identify endothelial secretion of ADAMTS5 and cleavage of versican as downstream mechanisms of CCM pathogenesis and provide a basis for the participation of wild-type endothelial cells in lesion formation. Competing Interests: Disclosures: L.E. Dow reported personal fees from Mirimus Inc. outside the submitted work. No other disclosures were reported. (© 2020 Hong et al.)
Databáze:	MEDLINE
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