Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations

Sci Rep. 2015 Nov 13:5:16449. doi: 10.1038/srep16449.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arteriovenous Malformations / genetics*
  • Arteriovenous Malformations / metabolism
  • Blotting, Western
  • CADASIL / genetics*
  • CADASIL / metabolism
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Endothelial Cells / ultrastructure
  • Gene Expression
  • HEK293 Cells
  • Humans
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Pericytes / metabolism*
  • Pericytes / pathology
  • Pericytes / ultrastructure
  • Receptor, Notch1 / deficiency
  • Receptor, Notch1 / genetics*
  • Receptor, Notch3
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Receptors, Notch / deficiency
  • Receptors, Notch / genetics*
  • Retinal Vessels / metabolism
  • Retinal Vessels / pathology
  • Retinal Vessels / physiopathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors

Substances

  • Notch1 protein, mouse
  • Notch3 protein, mouse
  • Receptor, Notch1
  • Receptor, Notch3
  • Receptors, Notch
  • Receptor, Platelet-Derived Growth Factor beta
  • Matrix Metalloproteinase 2