Cerebral arteriovenous malformations (AVMs) are common vascular malformations, 
which may result in hemorrhagic strokes and neurological deficits. Bone 
morphogenetic protein (BMP) and Notch signaling are both involved in the 
development of cerebral AVMs, but the cross-talk between the two signaling 
pathways is poorly understood. Here, we show that deficiency of matrix Gla 
protein (MGP), a BMP inhibitor, causes induction of Notch ligands, dysregulation 
of endothelial differentiation, and the development of cerebral AVMs in MGP null 
(Mgp(-/-)) mice. Increased BMP activity due to the lack of MGP induces 
expression of the activin receptor-like kinase 1, a BMP type I receptor, in 
cerebrovascular endothelium. Subsequent activation of activin receptor-like 
kinase 1 enhances expression of Notch ligands Jagged 1 and 2, which increases 
Notch activity and alters the expression of Ephrin B2 and Ephrin receptor B4, 
arterial and venous endothelial markers, respectively. Reducing the expression 
of Jagged 1 and 2 in the Mgp(-/-) mice by crossing them with Jagged 1 or 2 
deficient mice reduces Notch activity, normalizes endothelial differentiation, 
and prevents cerebral AVMs, but not pulmonary or renal AVMs. Our results suggest 
that Notch signaling mediates and can modulate changes in BMP signaling that 
lead to cerebral AVMs.