Published online before print May 15, 2008, doi: 10.1161/CIRCRESAHA.107.167965
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Submitted on November 20, 2007
Revised on April 28, 2008
Accepted on May 1, 2008
Notch Signaling Regulates Platelet-Derived Growth Factor Receptor-
Expression in Vascular Smooth Muscle Cells
Shaobo Jin ;
From the Department of Cell and Molecular Biology (S.J., E.M.H., F.L., C.S., F.F., U.L.), Medical Nobel Institute, Karolinska Institute, Stockholm, Sweden; Protein Chemistry Unit and Institute of Biomedicine/Anatomy (S.T., M.B.), University of Helsinki, Finland; and Department of Pathology (S.T., H.K.), University and University Hospital of Helsinki, Finland.
* To whom correspondence should be addressed. E-mail: Urban.Lendahl{at}ki.se.
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)-
is a novel immediate Notch target gene. PDGFR- expression was upregulated by Notch ligand induction or by activated forms of the Notch receptor. Moreover, upregulation of PDGFR- expression in response to Notch activation critically required the Notch signal integrator CSL. In primary VSMCs, PDGFR- expression was robustly upregulated by Notch signaling, leading to an augmented intracellular response to PDGF stimulation. In newborn Notch3-deficient mice, PDGFR- expression was strongly reduced in the VSMCs that later develop an aberrant morphology. In keeping with this, PDGFR- 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- 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.
Key words: PDGF • VSMC • CADASIL • vasculogenesis • angiogenesis
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