Role of endothelial to mesenchymal transition in the pathogenesis of the vascular alterations in systemic sclerosis

Abstract

The pathogenesis of Systemic Sclerosis (SSc) is extremely complex, and despite extensive studies, the exact mechanisms involved are not well understood. Numerous recent studies of early events in SSc pathogenesis have suggested that unknown etiologic factors in a genetically receptive host trigger structural and functional microvascular endothelial cell abnormalities. These alterations result in the attraction, transmigration, and accumulation of immune and inflammatory cells in the perivascular tissues, which in turn induce the phenotypic conversion of endothelial cells and quiescent fibroblasts into activated myofibroblasts, a process known as endothelial to mesenchymal transition or EndoMT. The activated myofibroblasts are the effector cells responsible for the severe and frequently progressive fibrotic process and the fibroproliferative vasculopathy that are the hallmarks of SSc. Thus, according to this hypothesis the endothelial and vascular alterations, which include the phenotypic conversion of endothelial cells into activated myofibroblasts, play a crucial role in the development of the progressive fibrotic process affecting skin and multiple internal organs. The role of endothelial cell and vascular alterations, the potential contribution of endothelial to mesenchymal cell transition in the pathogenesis of the tissue fibrosis, and fibroproliferative vasculopathy in SSc will be reviewed here.

Figure 1

Overall scheme illustrating a current understanding of SSc pathogenesis. Hypothetical sequence of events involved in tissue fibrosis and fibroproliferative vasculopathy in SSc. An unknown causative agent induces activation of immune and inflammatory cells in genetically predisposed hosts resulting in chronic inflammation. Activated inflammatory and immune cells secrete cytokines, chemokines, and growth factors which cause fibroblast activation, differentiation of endothelial and epithelial cells into myofibroblasts, and recruitment of fibrocytes from the bone marrow and the peripheral blood circulation. The activated myofibroblasts produce exaggerated amounts of ECM resulting in tissue fibrosis.

Figure 2

Histopathology of fibroproliferative vasculopathy in small vessels of various affected organs. Histopathology of microvascular arterioles from SSc lung, kidney, and retinal vessels displaying prominent endothelial fibroproliferative alterations causing severe narrowing of vessel lumen and thickening of vessel walls.

Figure 3

Signaling pathways involved in EndoMT. The diagram shows the numerous putative pathways that may participate in the EndoMT process and may be involved in SSc pathogenesis. One central pathway initiated following ligand-binding activation of the Smad-independent TGF-β pathway causes phosphorylation of GSK-3β mediated by PKC-δ and the c-Abl nonreceptor kinase. Phosphorylation of GSK-3β at serine 9 (ser9) causes its inhibition which then allows Snail-1 to enter the nucleus. Nuclear accumulation of Snail-1 results in marked stimulation of Snail-1 expression which then leads to acquisition of the myofibroblast phenotype with stimulation of α-SMA. The inhibition of GSK-3β ser9 phosphorylation by specific inhibition of PKC-δ or c-Abl activity allows GSK-3β to phosphorylate Snail-1 targeting it for proteosomal degradation and thus effectively abolishes the acquisition of the myofibroblastic phenotype and the fibrotic response. Other pathways such as those involving ET-1, Wnt, NOTCH, hypoxia, and cellular stress responses may also participate although the molecular events have not been fully elucidated. Modified from Piera-Velazquez and Jimenez [101].