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(Circulation Research. 2008;102:1483.)
© 2008 American Heart Association, Inc.

Molecular Medicine

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

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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				D. S. Weber A Novel Mechanism of Vascular Smooth Muscle Cell Regulation by Notch: Platelet-Derived Growth Factor Receptor-{beta} Expression? Circ. Res., June 20, 2008; 102(12): 1448 - 1450. [Full Text] [PDF]