title: Agonistic Anti-PDGF Receptor Autoantibodies from Patients with Systemic Sclerosis Impact Human Pulmonary Artery Smooth Muscle Cells FunctionIn Vitro.
abstract: One of the earliest events in the pathogenesis of systemic sclerosis (SSc) is microvasculature damage with intimal hyperplasia and accumulation of cells expressing PDGF receptor. Stimulatory autoantibodies targeting PDGF receptor have been detected in SSc patients and demonstrated to induce fibrosisin vivoand convertin vitronormal fibroblasts into SSc-like cells. Since there is no evidence of the role of anti-PDGF receptor autoantibodies in the pathogenesis of SSc vascular lesions, we investigated the biologic effect of agonistic anti-PDGF receptor autoantibodies from SSc patients on human pulmonary artery smooth muscle cells and the signaling pathways involved. The synthetic (proliferation, migration, and type I collagen gene α1 chain expression) and contractile (smooth muscle-myosin heavy chain and smooth muscle-calponin expression) profiles of human pulmonary artery smooth muscle cells were assessedin vitroafter incubation with SSc anti-PDGF receptors stimulatory autoantibodies. The role of reactive oxygen species, NOX isoforms, and mammalian target of rapamycin (mTOR) was investigated. Human pulmonary artery smooth muscle cells acquired a synthetic phenotype characterized by higher growth rate, migratory activity, gene expression of type I collagen α1 chain, and less expression of markers characteristic of the contractile phenotype such as smooth muscle-myosin heavy chain and smooth muscle-calponin when stimulated with PDGF and autoantibodies against PDGF receptor, but not with normal IgG. This phenotypic profile is mediated by increased generation of reactive oxygen species and expression of NOX4 and mTORC1. Our data indicate that agonistic anti-PDGF receptor autoantibodies may contribute to the pathogenesis of SSc intimal hyperplasia.
authors.affiliation: Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche , Ancona , Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Svegliati
authors.affiliation: Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche , Ancona , Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Amico
authors.affiliation: Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche , Ancona , Italy.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Spadoni
authors.affiliation: Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche , Ancona , Italy.
authors.forename: Colomba
authors.initials: C
authors.lastname: Fischetti
authors.affiliation: Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche , Ancona , Italy.
authors.forename: Doreen
authors.initials: D
authors.lastname: Finke
authors.affiliation: Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche , Ancona , Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Moroncini
authors.affiliation: Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche , Ancona , Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Paolini
authors.affiliation: Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche , Ancona , Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Tonnini
authors.affiliation: Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche , Ancona , Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Grieco
authors.affiliation: Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche , Ancona , Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Rovinelli
authors.affiliation: Dipartimento di Scienze Mediche, Università di Torino, Torino, Italy
authors.forename: Ada
authors.initials: A
authors.lastname: Funaro
authors.affiliation: Clinica Medica, Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche , Ancona , Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Gabrielli
keywords: autoantibodies; platelet derived growth factor; synthetic phenotype; systemic sclerosis; vascular smooth muscle cells