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Intravital Imaging of Disease Mechanisms in a Mouse Model of CCM Skin Lesions-Brief Report
Michael M Orlich1,2, Amanda Norrén1, Malavika Desai1
1Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden (M.M.O., A.N., M.D., H.S., T.M., K.G.).
Background:
Cerebral cavernous malformation (CCM) is a disease characterized by vascular malformations that primarily develop in the brain. These malformations are prone to leak, and their rupture or thrombotic closure can cause life-threatening hemorrhages and strokes. Mouse models have been instrumental to study the disease, but most cause premature lethality, precluding the investigation of disease mechanisms through intravital microscopy. Current mouse models also do not recapitulate human CCM skin lesions.
Methods:
Endothelial-specific deletion of Ccm3 via systemic tamoxifen application at postnatal day 4 or 5 prolongs survival and induces vascular malformations in the mouse brain and ear skin. CCM skin lesions can also be induced by topical tamoxifen administration directly to the ear. The thin, flat morphology of the ear skin is ideal for intravital microscopy. Dextran dyes and platelet markers allow to study blood flow and blood clot formation in living animals, in real time.
Results:
We report that human CCM skin lesions can be recapitulated in a mouse model and that skin lesions share hallmarks of CCM brain lesions. Intravital imaging reveals that CCM skin lesions are slow-flow malformations prone to thrombus formation.
Conclusions:
Intravital imaging of CCM skin lesions expands the toolkit of CCM research and allows longitudinal studies of lesion growth.
