Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells.
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.
Jin
Shaobo
S
Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, Stockholm, Sweden.
Hansson
Emil M
EM
Tikka
Saara
S
Lanner
Fredrik
F
Sahlgren
Cecilia
C
Farnebo
Filip
F
Baumann
Marc
M
Kalimo
Hannu
H
Lendahl
Urban
U
D000818:Animals; D000077214:Becaplermin; D046589:CADASIL / Q000235:genetics; D002465:Cell Movement; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology; D006801:Humans; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology / Q000502:physiology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology; D000071656:Receptor, Notch3; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000502:physiology*; D051880:Receptors, Notch / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
C499374:NOTCH3 protein, human; C497762:Notch1 protein, mouse; C499373:Notch3 protein, mouse; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta