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Schwefel, K.* ; Spiegler, S.* ; Kirchmaier, B.C.* ; Dellweg, P.K.E.* ; Much, C.D.* ; Pané-Farré, J.* ; Strom, T.M. ; Riedel, K.* ; Felbor, U.* ; Rath, M.*

Fibronectin rescues aberrant phenotype of endothelial cells lacking either CCM1, CCM2 or CCM3.

FASEB J. 34, 9018-9033 (2020)
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Open Access Gold (Paid Option)
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Loss-of-function variants in CCM1/KRIT1, CCM2, and CCM3/PDCD10 are associated with autosomal dominant cerebral cavernous malformations (CCMs). CRISPR/Cas9-mediated CCM3 inactivation in human endothelial cells (ECs) has been shown to induce profound defects in cell-cell 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-like structures nor inhibited the survival advantage of CCM3(-/-) ECs. Importantly, CRISPR/Cas9-mediated introduction of biallelic loss-of-function variants into either CCM1 or CCM2 demonstrated that the impaired production of a functional fibronectin matrix is a common feature of CCM1-, CCM2-, and CCM3-deficient ECs.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Cerebral Cavernous Malformations ; Crispr ; Cas9 Genome Editing ; Extracellular Matrix; Cerebral Cavernous Malformations; Vascular Morphogenesis; Integrin Alpha-5-beta-1; Extracellular-matrix; Binding Domain; Rho Kinase; Mutations; Proteins; Barrier; Angiogenesis
ISSN (print) / ISBN 0892-6638
e-ISSN 1530-6860
Journal FASEB Journal
Quellenangaben Volume: 34, Issue: 7, Pages: 9018-9033 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Bethesda, Md.
Reviewing status Peer reviewed