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New Insights into Profibrotic Myofibroblast Formation in Systemic Sclerosis: When the Vascular Wall Becomes the Enemy
Eloisa Romano1, Irene Rosa2, Bianca Saveria Fioretto1
1Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, 50134 Florence, Italy.
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.
Insights
Systemic sclerosis (SSc) involves early microvessel abnormalities and fibrosis. Endothelial-to-mesenchymal transition (EndoMT) is a key driver, where endothelial cells transform into myofibroblasts, causing vascular damage and tissue fibrosis in SSc.
Area of Science:
- Vascular Biology
- Fibrosis Research
- Systemic Sclerosis Pathogenesis
Background:
- Systemic sclerosis (SSc) is characterized by early microvessel abnormalities and progressive tissue fibrosis.
- A close relationship exists between SSc-related vasculopathy and fibrosis, with myofibroblasts playing a central role.
- Recent insights highlight the significance of endothelial-to-mesenchymal transition (EndoMT) in SSc.
Purpose of the Study:
- To elucidate the role of endothelial-to-mesenchymal transition (EndoMT) in the pathogenesis of systemic sclerosis (SSc).
- To explore how EndoMT contributes to both vascular lesions and tissue fibrosis in SSc.
- To identify potential therapeutic targets by understanding myofibroblast differentiation in SSc.
Main Methods:
- Review and synthesis of current literature on SSc, vasculopathy, fibrosis, and EndoMT.
- Analysis of cellular and molecular mechanisms involved in myofibroblast generation from vascular cells.
- Examination of the distinct roles of EndoMT in different vessel types (arterioles vs. capillaries) in SSc.
Main Results:
- Endothelial-to-mesenchymal transition (EndoMT) is increasingly recognized as a central mechanism in SSc pathogenesis.
- In SSc, EndoMT contributes to fibroproliferative vascular lesions in larger vessels and vascular destruction/fibrosis in capillaries.
- Other vascular cells like pericytes and smooth muscle cells can also adopt myofibroblast phenotypes, exacerbating SSc pathology.
Conclusions:
- Endothelial-to-mesenchymal transition (EndoMT) is a critical process driving both vasculopathy and fibrosis in systemic sclerosis (SSc).
- Understanding the mechanisms of myofibroblast differentiation in SSc offers a basis for developing targeted therapies.
- Targeting EndoMT and related cellular transformations presents a promising avenue for treating SSc.
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