RESUMO
Platelet-derived growth factor (PDGF) acts through two conserved receptor tyrosine kinases: PDGFRα and PDGFRß. Gain-of-function mutations in human PDGFRB have been linked recently to genetic diseases characterized by connective tissue wasting (Penttinen syndrome) or overgrowth (Kosaki overgrowth syndrome), but it is unclear whether PDGFRB mutations alone are responsible. Mice with constitutive PDGFRß signaling caused by a kinase domain mutation (D849V) develop lethal autoinflammation. Here we used a genetic approach to investigate the mechanism of autoinflammation in Pdgfrb+/D849V mice and test the hypothesis that signal transducer and activator of transcription 1 (STAT1) mediates this phenotype. We show that Pdgfrb+/D849V mice with Stat1 knockout (Stat1-/-Pdgfrb+/D849V ) are rescued from autoinflammation and have improved life span compared with Stat1+/-Pdgfrb+/D849V mice. Furthermore, PDGFRß-STAT1 signaling suppresses PDGFRß itself. Thus, Stat1-/-Pdgfrb+/D849V fibroblasts exhibit increased PDGFRß signaling, and mice develop progressive overgrowth, a distinct phenotype from the wasting seen in Stat1+/-Pdgfrb+/D849V mice. Deletion of interferon receptors (Ifnar1 or Ifngr1) does not rescue wasting in Pdgfrb+/D849V mice, indicating that interferons are not required for autoinflammation. These results provide functional evidence that elevated PDGFRß signaling causes tissue wasting or overgrowth reminiscent of human genetic syndromes and that the STAT1 pathway is a crucial modulator of this phenotypic spectrum.
Assuntos
Transtornos do Crescimento/genética , Mutação , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Fator de Transcrição STAT1/genética , Tecido Adiposo/patologia , Animais , Aorta/patologia , Atrofia , Osso e Ossos/anormalidades , Feminino , Fibroblastos/metabolismo , Fibrose , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Hiperplasia , Inflamação/metabolismo , Interferons/fisiologia , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/patologia , Células NIH 3T3 , Fenótipo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais , Pele/patologiaRESUMO
Signal transducer and activator of transcription 1 (Stat1) is a ubiquitously expressed latent transcription factor that is activated by many cytokines and growth factors. Global Stat1 knockout mice are prone to chemical-induced lung and liver fibrosis, suggesting roles for Stat1 in tissue repair. However, the importance of Stat1 in fibroblast-mediated and vascular smooth muscle cell (VSMC)-mediated injury response has not been directly evaluated in vivo. Here, we focused on two models of tissue repair in conditional Stat1 knockout mice: excisional skin wounding in mice with Stat1 deletion in dermal fibroblasts, and carotid artery ligation in mice with global Stat1 deletion or deletion specific to VSMCs. In the skin model, dermal wounds closed at a similar rate in mice with fibroblast Stat1 deletion and controls, but collagen and α-smooth muscle actin (αSMA) expression were increased in the mutant granulation tissue. Cultured Stat1 -/- and Stat1 +/- dermal fibroblasts exhibited similar αSMA+ stress fiber assembly, collagen gel contraction, proliferation, migration, and growth factor-induced gene expression. In the artery ligation model, there was a significant increase in fibroblast-driven perivascular fibrosis when Stat1 was deleted globally. However, VSMC-driven remodeling and neointima formation were unchanged when Stat1 was deleted specifically in VSMCs. These results suggest an in vivo role for Stat1 as a suppressor of fibroblast mediated, but not VSMC mediated, injury responses, and a suppressor of the myofibroblast phenotype.
Assuntos
Artérias Carótidas/metabolismo , Fibroblastos/metabolismo , Miócitos de Músculo Liso/metabolismo , Miofibroblastos/metabolismo , Reepitelização/genética , Fator de Transcrição STAT1/genética , Pele/metabolismo , Actinas/metabolismo , Animais , Lesões das Artérias Carótidas/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Colágeno/metabolismo , Regulação da Expressão Gênica/genética , Tecido de Granulação/metabolismo , Camundongos , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Fenótipo , Cicatrização/genéticaRESUMO
Platelet-derived growth factor (PDGF) is a mitogen and chemoattractant for vascular smooth muscle cells (VSMCs). However, the direct effects of PDGF receptor ß (PDGFRß) activation on VSMCs have not been studied in the context of atherosclerosis. Here we present a new mouse model of atherosclerosis with an activating mutation in PDGFRß. Increased PDGFRß signalling induces chemokine secretion and leads to leukocyte accumulation in the adventitia and media of the aorta. Furthermore, PDGFRß(D849V) amplifies and accelerates atherosclerosis in hypercholesterolemic ApoE(-/-) or Ldlr(-/-) mice. Intriguingly, increased PDGFRß signalling promotes advanced plaque formation at novel sites in the thoracic aorta and coronary arteries. However, deletion of the PDGFRß-activated transcription factor STAT1 in VSMCs alleviates inflammation of the arterial wall and reduces plaque burden. These results demonstrate that PDGFRß pathway activation has a profound effect on vascular disease and support the conclusion that inflammation in the outer arterial layers is a driving process for atherosclerosis.