Publication: Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations.
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2015-11-13
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Nature Publishing Group
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Abstract
Pericytes regulate vessel stability and pericyte dysfunction contributes to retinopathies, stroke, and cancer. Here we define Notch as a key regulator of pericyte function during angiogenesis. In Notch1(+/-); Notch3(-/-) mice, combined deficiency of Notch1 and Notch3 altered pericyte interaction with the endothelium and reduced pericyte coverage of the retinal vasculature. Notch1 and Notch3 were shown to cooperate to promote proper vascular basement membrane formation and contribute to endothelial cell quiescence. Accordingly, loss of pericyte function due to Notch deficiency exacerbates endothelial cell activation caused by Notch1 haploinsufficiency. Mice mutant for Notch1 and Notch3 develop arteriovenous malformations and display hallmarks of the ischemic stroke disease CADASIL. Thus, Notch deficiency compromises pericyte function and contributes to vascular pathologies.
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Animals Arteriovenous Malformations Blotting, Western CADASIL Cell Differentiation Cells, Cultured Disease Models, Animal Endothelial Cells Gene Expression HEK293 Cells Humans Matrix Metalloproteinase 2 Mice, Inbred C57BL Mice, Knockout Microscopy, Confocal Microscopy, Electron, Transmission Muscle, Smooth, Vascular Pericytes Receptor, Notch1 Receptor, Notch3 Receptor, Platelet-Derived Growth Factor beta Receptors, Notch Retinal Vessels Reverse Transcriptase Polymerase Chain Reaction Time Factors
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Sci Rep. 2015 Nov 13:5:16449.