Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican

Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1084/jem.20200140
Journal or Publication Title: Journal of Experimental Medicine
Volume: 217
Number: 10
Date: 2020
Divisions: Vascular Biology
Depositing User: General Admin
Identification Number: 10.1084/jem.20200140
ISSN: 0022-1007
Date Deposited: 04 Jan 2021 02:49
Abstract:

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.

Creators:
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Hong, Courtney C.
UNSPECIFIED
Tang, Alan T.
UNSPECIFIED
Detter, Matthew R.
UNSPECIFIED
Choi, Jaesung P.
UNSPECIFIED
Wang, Rui
UNSPECIFIED
Yang, Xi
UNSPECIFIED
Guerrero, Andrea A.
UNSPECIFIED
Wittig, Carl F.
UNSPECIFIED
Hobson, Nicholas
UNSPECIFIED
Girard, Romuald
UNSPECIFIED
Lightle, Rhonda
UNSPECIFIED
Moore, Thomas
UNSPECIFIED
Shenkar, Robert
UNSPECIFIED
Polster, Sean P.
UNSPECIFIED
Goddard, Lauren M.
UNSPECIFIED
Ren, Aileen A.
UNSPECIFIED
Leu, N. Adrian
UNSPECIFIED
Sterling, Stephanie
UNSPECIFIED
Yang, Jisheng
UNSPECIFIED
Li, Li
UNSPECIFIED
Chen, Mei
UNSPECIFIED
Mericko-Ishizuka, Patricia
UNSPECIFIED
Dow, Lukas E.
UNSPECIFIED
Watanabe, Hideto
UNSPECIFIED
Schwaninger, Markus
UNSPECIFIED
Min, Wang
UNSPECIFIED
Marchuk, Douglas A.
UNSPECIFIED
Zheng, Xiangjian
UNSPECIFIED
Awad, Issam A.
UNSPECIFIED
Kahn, Mark L.
UNSPECIFIED
Last Modified: 04 Jan 2021 02:49
URI: https://eprints.centenary.org.au/id/eprint/762

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