title: Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency.
abstract: 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.
authors.affiliation: Division of Cardiology, David Geffen School of Medicine at UCLA and Molecular Biology Institute, University of California, Los Angeles, CA 90095-1679.
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Yao
authors.forename: Jiayi
authors.initials: J
authors.lastname: Yao
authors.forename: Melina
authors.initials: M
authors.lastname: Radparvar
authors.forename: Ana M
authors.initials: AM
authors.lastname: Blazquez-Medela
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Guihard
authors.forename: Medet
authors.initials: M
authors.lastname: Jumabay
authors.forename: Kristina I
authors.initials: KI
authors.lastname: Boström
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors; D002135:Calcium-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology; D036388:Ephrin-B2 / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000235:genetics; D017353:Gene Deletion; D051528:Guanylate Kinases / Q000378:metabolism*; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D002538:Intracranial Arteriovenous Malformations / Q000209:etiology* / Q000517:prevention & control*; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D036081:Receptors, Eph Family / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D055114:X-Ray Microtomography; D000097568:Matrix Gla Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D036388:Ephrin-B2; D016326:Extracellular Matrix Proteins; D051528:Guanylate Kinases; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D036081:Receptors, Eph Family; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D000097568:Matrix Gla Protein; C000606274:Jag1 protein, mouse; C490503:Jag2 protein, mouse; C405684:Magi2 protein, mouse
keywords: angiogenesis; animal model; brain circulation; hereditary hemorrhagic telangiectasia; shunt