Rationale: 

Cerebral cavernous malformations (CCM) are benign vascular tumours affecting 0.1 - 0.5% of the population. CCM lesions consist of thin-walled and grossly dilated capillary-like sinusoidal blood vessels lacking pericytes and contacts with astrocytes. CCM is caused by mutations in one of the three CCM genes. CCM1 (also known as KRIT1) is essential for blood vessel remodelling, cell junctions and cell polarity. The early steps of CCM pathogenesis remain unknown.

Methodology: 

siRNA and shRNA-mediated silencing of CCM1 and ICAP1 in primary human endothelial cells. Adenoviral and lentiviral overexpression. Microarray analyses, qPCR, Western blotting. Transplantation of genetically modified human endothelial cells into immunocompromised mice.

Results: 

We could show that CCM1 and its interacting partner ICAP1 represent anti-angiogenic proteins to keep the endothelium quiescent. CCM1 inhibits endothelial proliferation, apoptosis, migration and sprouting angiogenesis. CCM1 and ICAP1 induce Delta-NOTCH signalling which promotes Protein kinase B (AKT) and reduces ERK phosphorylation. Blocking of NOTCH activity alleviates CCM1 effects. CCM1-silenced human endothelial cells form a hyperdense vascular network with increased lumen diameters after subcutaneous transplantation into immunocompromised mice. The receptor-tyrosine-kinase inhibitor Sorafenib causes regression of the excessive vasculature. Thus, this novel CCM model does not only recapitulate hallmarks of the CCM pathology but also serves as a drug testing system.

Conclusions: 

The results suggest that cerebral cavernous malformations are caused by uncontrolled angiogenesis. Anti-angiogenic therapy might become a first non-surgical treatment option. Supported by the Deutsche Forschungsgemeinschaft DFG (SFB-TR23; GRK880)