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.

BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus

“…Indeed, although TGFβ is one of the most potent inducers of EMT (14), the role of BMPs is still not completely clear (25). BMPs have been described as either inhibitors of endMT (BMP7 in cardiac fibrosis) (26) or inducers of endMT [BMP6 in cerebral cavernous malformations (27) and BMP2 in cardiac valve formation (28)]. BMP9 has been recently shown to induce EMT in hepatocellular carcinoma cells (29), and our data support that BMP9 and BMP10 can also induce endMT.…”

Molecular and Genetic Basis of Cerebral Cavernous Malformations

“…CCM1'in fonksiyonel kaybı, Notch sinyal iletimini hasara uğratmakta ve oluşan bu hasar durumu da BMP6 (kemik morfojenik proteini 6) miktarında artışla ortaya çıkmaktadır. BMP6'nın hücrede artışı, TGF-ß (transforme edici büyüme faktörü ß) molekülünü ve BMP sinyal yolağını aktive eder ve endotelyal mezenşimal dönüşümün artmasını tetiklemektedir (28).…”

CCM1 and the second life of proteins in adhesion complexes

“…109,110 By use of an endothelial-specific tamoxifeninducible Ccm1 loss of function mice (iCCM1), it was demonstrated that the endothelial cells lining the vascular lesions associated with CCM, showed highly disorganized VE-cadherin expression and upregulated N-cadherin expression. 111 Furthermore, CCM1 downregulation in lung and brain microvascular endothelial cells showed increased proliferation and enhanced invasive/ sprouting capacitiy, which is mediated by Notch inhibition and subsequent BMP6 (bone morphogenetic protein 6) upregulation. Upregulation of BMP6 activates transforming growth factor-β (TGF-β) and BMP signaling pathways and results in increased EndMT.…”

“…Upregulation of BMP6 activates transforming growth factor-β (TGF-β) and BMP signaling pathways and results in increased EndMT. 111 As Wnt/β-catenin signaling plays an important role in EndMT in myocardial cells 112 and loss of CCM1 enhances β-catenin-dependent activation of the Wnt signaling pathway, 68 this might be another pathway that contributes the EndMT phenotype.…”