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 fibrosis in vivo and convert in vitro normal 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 assessed in vitro after 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.
Highlights
IntroductionSystemic sclerosis (SSc; scleroderma) is a multiorgan disorder characterized by microvasculature damage, circulating autoantibodies, and fibroblast activation leading to fibrosis of the skin and visceral organs [1,2,3]
Systemic sclerosis (SSc; scleroderma) is a multiorgan disorder characterized by microvasculature damage, circulating autoantibodies, and fibroblast activation leading to fibrosis of the skin and visceral organs [1,2,3].Vascular involvement is an early and very likely primary event in the pathogenesis of scleroderma, precedes fibrosis, and is characterized by endothelial cell (EC) injury and dysfunction, altered capillary permeability, increased expression of adhesion molecules, abnormal secretion of vasoactive mediators, and activation of platelets and fibrinolytic pathways [4,5,6,7]
Since the pathogenesis of scleroderma is characterized by an abnormal generation of reactive oxygen species (ROS) [for review, see Ref. [34]] and several lines of evidence implicate oxidative stress in the pathogenesis of PAH [35], we exploited our previous demonstration that agonistic anti-PDGFRα autoantibodies isolated from systemic sclerosis (SSc) sera induce an abnormal generation of ROS in normal fibroblasts via NOX [23, 24, 36]
Summary
Systemic sclerosis (SSc; scleroderma) is a multiorgan disorder characterized by microvasculature damage, circulating autoantibodies, and fibroblast activation leading to fibrosis of the skin and visceral organs [1,2,3]. Vascular involvement is an early and very likely primary event in the pathogenesis of scleroderma, precedes fibrosis, and is characterized by endothelial cell (EC) injury and dysfunction, altered capillary permeability, increased expression of adhesion molecules, abnormal secretion of vasoactive mediators, and activation of platelets and fibrinolytic pathways [4,5,6,7]. A further mechanisms has been reported by Riemekasten et al who detected serum autoantibodies against angiotensin II type I receptor and endothelin-1 type 1 receptor, which induced extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation and increased TGF-β gene expression in ECs and were associated with severe disease manifestations [15]
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