Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency

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 p...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-11, Vol.110 (47), p.19071-19076
Main Authors: Yao, Yucheng, Yao, Jiayi, Radparvar, Melina, Blazquez-Medela, Ana M., Guihard, Pierre J., Jumabay, Medet, Boström, Kristina I.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Analysis of Variance
Animals
Arteriovenous malformations
Biological Sciences
Bone Morphogenetic Proteins - antagonists & inhibitors
Calcium-Binding Proteins - deficiency
Calcium-Binding Proteins - genetics
Calcium-Binding Proteins - metabolism
Cardiovascular system
Cell Differentiation - physiology
Endothelial cells
Endothelial Cells - physiology
Ephrin-B2 - metabolism
Ephrins
Extracellular Matrix Proteins - deficiency
Extracellular Matrix Proteins - genetics
Gene Deletion
Gene expression
Guanylate Kinases - metabolism
Immunoblotting
Intercellular Signaling Peptides and Proteins - metabolism
Intracranial Arteriovenous Malformations - etiology
Intracranial Arteriovenous Malformations - prevention & control
Jagged-1 Protein
Jagged-2 Protein
Kidneys
Ligands
Lungs
Matrix Gla Protein
Membrane Proteins - metabolism
Mice
Mice, Knockout
Molecules
Neurology
Proteins
Real-Time Polymerase Chain Reaction
Receptors, Eph Family - metabolism
Receptors, Notch - metabolism
RNA, Small Interfering - genetics
Serrate-Jagged Proteins
Signal transduction
Small interfering RNA
Transfection
Veins & arteries
X-Ray Microtomography
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1310905110