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Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells
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2008 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 102, no 12, 1483-1491 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2008. Vol. 102, no 12, 1483-1491 p.
National Category
Neurology Cell and Molecular Biology
Research subject
Neurology; Pathology
URN: urn:nbn:se:uu:diva-126006DOI: 10.1161/CIRCRESAHA.107.167965PubMedID: 18483410OAI: oai:DiVA.org:uu-126006DiVA: diva2:321614
Available from: 2010-06-01 Created: 2010-06-01 Last updated: 2010-07-27Bibliographically approved

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