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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.<\/jats:p>","DOI":"10.1084\/jem.20200140","type":"journal-article","created":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T02:21:28Z","timestamp":1590027688000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican"],"prefix":"10.1084","volume":"217","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0515-6816","authenticated-orcid":true,"given":"Courtney C.","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan 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