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

Shaobo Jin, Emil M. Hansson, Saara Tikka, Fredrik Lanner, Cecilia Sahlgren, Filip Farnebo, Marc Baumann, Hannu Kalimo, Urban Lendahl*

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

121 Citations (Scopus)

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)-β is a novel immediate Notch target gene. PDGFR-β expression was upregulated by Notch ligand induction or by activated forms of the Notch receptor. Moreover, upregulation of PDGFR-β expression in response to Notch activation critically required the Notch signal integrator CSL. In primary VSMCs, PDGFR-β expression was robustly upregulated by Notch signaling, leading to an augmented intracellular response to PDGF stimulation. In newborn Notch3-deficient mice, PDGFR-β expression was strongly reduced in the VSMCs that later develop an aberrant morphology. In keeping with this, PDGFR-β 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-β 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.

Original languageEnglish
Pages (from-to)1483-1491
Number of pages9
JournalCirculation Research
Volume102
Issue number12
DOIs
Publication statusPublished - 20 Jun 2008
Externally publishedYes
MoE publication typeA1 Journal article-refereed

Keywords

  • Angiogenesis
  • CADASIL
  • PDGF
  • Vasculogenesis
  • VSMC

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