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Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels #MMPMID25468970
Murphy PA; Kim TN; Huang L; Nielsen CM; Lawton MT; Adams RH; Schaffer CB; Wang RA
Proc Natl Acad Sci U S A 2014[Dec]; 111 (50): 18007-12 PMID25468970show ga
Brain arteriovenous malformations are focal lesions of enlarged, tangled vessels that shunt blood from arteries directly to veins. They can cause ischemia, hemorrhage, disability, and death, particularly in young people, accounting for 50% of childhood stroke. The molecular etiology of the disease remains poorly understood, hindering the development of therapeutic treatments. Here, we report that, in an animal model, the lesion arises from the enlargement of capillary-like vessels. Notch signaling in the endothelium of microvasculature and veins is critical for the disease initiation by increasing cell areas but not proliferation. Blood flow mediates disease progression by a positive feedback of increasing flow and vessel diameter. Our data shed light on the mechanism underlying the pathogenesis of this devastating disease.