title: EndMT contributes to the onset and progression of cerebral cavernous malformations.
abstract: Cerebral cavernous malformation (CCM) is a vascular dysplasia, mainly localized within the brain and affecting up to 0.5% of the human population. CCM lesions are formed by enlarged and irregular blood vessels that often result in cerebral haemorrhages. CCM is caused by loss-of-function mutations in one of three genes, namely CCM1 (also known as KRIT1), CCM2 (OSM) and CCM3 (PDCD10), and occurs in both sporadic and familial forms. Recent studies have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear. Postnatal deletion of any of the three Ccm genes in mouse endothelium results in a severe phenotype, characterized by multiple brain vascular malformations that are markedly similar to human CCM lesions. Endothelial-to-mesenchymal transition (EndMT) has been described in different pathologies, and it is defined as the acquisition of mesenchymal- and stem-cell-like characteristics by the endothelium. Here we show that endothelial-specific disruption of the Ccm1 gene in mice induces EndMT, which contributes to the development of vascular malformations. EndMT in CCM1-ablated endothelial cells is mediated by the upregulation of endogenous BMP6 that, in turn, activates the transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling pathway. Inhibitors of the TGF-β and BMP pathway prevent EndMT both in vitro and in vivo and reduce the number and size of vascular lesions in CCM1-deficient mice. Thus, increased TGF-β and BMP signalling, and the consequent EndMT of CCM1-null endothelial cells, are crucial events in the onset and progression of CCM disease. These studies offer novel therapeutic opportunities for this severe, and so far incurable, pathology.
authors.affiliation: IFOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy. uigi.maddaluno@ifom.eu
authors.forename: Luigi
authors.initials: L
authors.lastname: Maddaluno
authors.forename: Noemi
authors.initials: N
authors.lastname: Rudini
authors.forename: Roberto
authors.initials: R
authors.lastname: Cuttano
authors.forename: Luca
authors.initials: L
authors.lastname: Bravi
authors.forename: Costanza
authors.initials: C
authors.lastname: Giampietro
authors.forename: Monica
authors.initials: M
authors.lastname: Corada
authors.forename: Luca
authors.initials: L
authors.lastname: Ferrarini
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Orsenigo
authors.forename: Eleanna
authors.initials: E
authors.lastname: Papa
authors.forename: Gwenola
authors.initials: G
authors.lastname: Boulday
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Tournier-Lasserve
authors.forename: Françoise
authors.initials: F
authors.lastname: Chapon
authors.forename: Cristina
authors.initials: C
authors.lastname: Richichi
authors.forename: Saverio Francesco
authors.initials: SF
authors.lastname: Retta
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Lampugnani
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
mesh_terms: D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics / Q000473:pathology*; D006801:Humans; D000075927:KRIT1 Protein; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D055418:Bone Morphogenetic Protein 6; D000075927:KRIT1 Protein; C491535:Krit1 protein, mouse; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta