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

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.

journal_name

Circ Res

journal_title

Circulation research

authors

Jin S,Hansson EM,Tikka S,Lanner F,Sahlgren C,Farnebo F,Baumann M,Kalimo H,Lendahl U

doi

10.1161/CIRCRESAHA.107.167965

subject

Has Abstract

pub_date

2008-06-20 00:00:00

pages

1483-91

issue

12

eissn

0009-7330

issn

1524-4571

pii

CIRCRESAHA.107.167965

journal_volume

102

pub_type

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