Published online before print May 15, 2008, doi: 10.1161/CIRCRESAHA.107.167965
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© 2008 American Heart Association, Inc.
Molecular Medicine |
Notch Signaling Regulates Platelet-Derived Growth Factor Receptor-β Expression in Vascular Smooth Muscle Cells
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.
Correspondence to Urban Lendahl, Department of Cell and Molecular Biology, Karolinska Institute, von Eulers väg 3, SE-171 77 Stockholm, Sweden. 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)-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.
Key Words: PDGF • VSMC • CADASIL • vasculogenesis • angiogenesis
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