Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells

Circ Res. 2008 Jun 20;102(12):1483-91. doi: 10.1161/CIRCRESAHA.107.167965. Epub 2008 May 15.

Abstract

Notch signaling is critically important for proper architecture of the vascular system, and mutations in NOTCH3 are associated with CADASIL, a stroke and dementia syndrome with vascular smooth muscle cell (VSMC) dysfunction. In this report, we link Notch signaling to platelet-derived growth factor (PDGF) signaling, a key determinant of VSMC biology, and show that PDGF receptor (PDGFR)-beta is a novel immediate Notch target gene. PDGFR-beta expression was upregulated by Notch ligand induction or by activated forms of the Notch receptor. Moreover, upregulation of PDGFR-beta expression in response to Notch activation critically required the Notch signal integrator CSL. In primary VSMCs, PDGFR-beta expression was robustly upregulated by Notch signaling, leading to an augmented intracellular response to PDGF stimulation. In newborn Notch3-deficient mice, PDGFR-beta expression was strongly reduced in the VSMCs that later develop an aberrant morphology. In keeping with this, PDGFR-beta upregulation in response to Notch activation was reduced also in Notch3-deficient embryonic stem cells. Finally, in VSMCs from a CADASIL patient carrying a NOTCH3 missense mutation, upregulation of PDGFR-beta mRNA and protein in response to ligand-induced Notch activation was significantly reduced. In sum, these data reveal a hierarchy for 2 important signaling systems, Notch and PDGF, in the vasculature and provide insights into how dysregulated Notch signaling perturbs VSMC differentiation and function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Becaplermin
  • CADASIL / genetics
  • Cell Movement
  • Cells, Cultured / cytology
  • Cells, Cultured / drug effects
  • Cells, Cultured / physiology
  • Embryonic Stem Cells / cytology
  • Humans
  • Mice
  • Muscle, Smooth, Vascular / cytology*
  • Myocytes, Smooth Muscle / cytology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / physiology*
  • Platelet-Derived Growth Factor / pharmacology
  • Platelet-Derived Growth Factor / physiology
  • Proto-Oncogene Proteins c-sis
  • Rats
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / physiology
  • Receptor, Notch3
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Receptor, Platelet-Derived Growth Factor beta / physiology*
  • Receptors, Notch / deficiency
  • Receptors, Notch / genetics
  • Receptors, Notch / physiology*
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*

Substances

  • NOTCH3 protein, human
  • Notch1 protein, mouse
  • Notch3 protein, mouse
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Receptor, Notch1
  • Receptor, Notch3
  • Receptors, Notch
  • Recombinant Fusion Proteins
  • Becaplermin
  • Receptor, Platelet-Derived Growth Factor beta