New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy

Abstract

In systemic sclerosis (SSc), abnormalities in microvessel morphology occur early and evolve into a distinctive vasculopathy that relentlessly advances in parallel with the development of tissue fibrosis orchestrated by myofibroblasts in nearly all affected organs. Our knowledge of the cellular and molecular mechanisms underlying such a unique relationship between SSc-related vasculopathy and fibrosis has profoundly changed over the last few years. Indeed, increasing evidence has suggested that endothelial-to-mesenchymal transition (EndoMT), a process in which profibrotic myofibroblasts originate from endothelial cells, may take center stage in SSc pathogenesis. While in arterioles and small arteries EndoMT may lead to the accumulation of myofibroblasts within the vessel wall and development of fibroproliferative vascular lesions, in capillary vessels it may instead result in vascular destruction and formation of myofibroblasts that migrate into the perivascular space with consequent tissue fibrosis and microvessel rarefaction, which are hallmarks of SSc. Besides endothelial cells, other vascular wall-resident cells, such as pericytes and vascular smooth muscle cells, may acquire a myofibroblast-like synthetic phenotype contributing to both SSc-related vascular dysfunction and fibrosis. A deeper understanding of the mechanisms underlying the differentiation of myofibroblasts inside the vessel wall provides the rationale for novel targeted therapeutic strategies for the treatment of SSc.