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CRISPR\/Cas9\u2010mediated CCM3 inactivation in human endothelial cells (ECs) has been shown to induce profound defects in cell\u2010cell interaction as well as actin cytoskeleton organization. We here show that CCM3 inactivation impairs fibronectin expression and consequently leads to reduced fibers in the extracellular matrix. Despite the complexity and high molecular weight of fibronectin fibrils, our in vitro model allowed us to reveal that fibronectin supplementation restored aberrant spheroid formation as well as altered EC morphology, and suppressed actin stress fiber formation. Yet, fibronectin replacement neither enhanced the stability of tube\u2010like structures nor inhibited the survival advantage of\n                    <jats:italic>\n                      CCM3\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    ECs. Importantly, CRISPR\/Cas9\u2010mediated introduction of biallelic loss\u2010of\u2010function variants into either\n                    <jats:italic>CCM1<\/jats:italic>\n                    or\n                    <jats:italic>CCM2<\/jats:italic>\n                    demonstrated that the impaired production of a functional fibronectin matrix is a common feature of CCM1\u2010, CCM2\u2010, and CCM3\u2010deficient ECs.\n                  <\/jats:p>","DOI":"10.1096\/fj.201902888r","type":"journal-article","created":{"date-parts":[[2020,7,27]],"date-time":"2020-07-27T10:37:08Z","timestamp":1595846228000},"page":"9018-9033","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Fibronectin rescues aberrant phenotype of endothelial cells lacking either CCM1, CCM2 or CCM3"],"prefix":"10.1096","volume":"34","author":[{"given":"Konrad","family":"Schwefel","sequence":"first","affiliation":[{"name":"Department of Human Genetics University Medicine Greifswald Greifswald Germany"},{"name":"Interfaculty Institute of Genetics and Functional Genomics University of Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Spiegler","sequence":"additional","affiliation":[{"name":"Department of Human Genetics University Medicine Greifswald Greifswald Germany"},{"name":"Interfaculty Institute of Genetics and Functional Genomics University of Greifswald Greifswald Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina C.","family":"Kirchmaier","sequence":"additional","affiliation":[{"name":"Institute of Cell Biology and Neuroscience University of Frankfurt Frankfurt am Main Germany"},{"name":"Buchmann Institute for Molecular Life Sciences University of Frankfurt Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia K. 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