What is the role of vascular alterations in the pathogenesis of scleroderma?

Updated: Jun 24, 2020
  • Author: Sergio A Jimenez, MD, MACR, FACP, FRCP(UK Hon); Chief Editor: Herbert S Diamond, MD  more...
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The vascular alterations preferentially affect small arteries and arterioles. Vascular dysfunction is one of the earliest alterations of systemic sclerosis. Severe alterations in small blood vessels of skin and internal organs, including endothelial dysfunction, subendothelial fibrosis, and perivascular cellular infiltration with activated T cells and macrophages, are almost universally present in systemic sclerosis affected tissues. [8]

Recent evidence supports the concept that endothelial dysfunction and fibrosis are closely related phenomena and it has been suggested that the vascular alterations, including the phenotypic conversion of endothelial cells into activated mesenchymal myofibroblasts, may be the initiating event and the common pathogenetic alteration leading to the fibrotic and chronic inflammatory involvement of multiple organs. [8, 9]

The activation of endothelial cells induces the expression of chemokines and cell adhesion molecules, causes the attraction, transendothelial migration, and perivascular accumulation of immunologic-inflammatory cells, including T- and B-lymphocytes and macrophages. The inflammatory cells produce and secrete a variety of cytokines and/or growth factors including transforming growth factor beta (TGF-β) and other profibrotic mediators such as endothelin-1, which induce increased proliferation of smooth muscle cells, marked accumulation of subendothelial fibrotic tissue, and initiation of platelet aggregation and intravascular thrombosis, eventually causing microvascular occlusion.

The fibrotic process is characterized by the excessive production and deposition of types I, III, and VI collagens and other ECM and connective tissue macromolecules including COMP, glycosaminoglycans, tenascin, and fibronectin. [10, 11] This crucial component results from the accumulation in skin and other affected tissues of myofibroblasts, cells possessing unique biological functions, including increased production of fibrillar type I and type III collagens, expression of α-smooth muscle actin, and reduction in the expression of genes encoding ECM–degradative enzymes. Thus, the accumulation of myofibroblasts in affected tissues and the uncontrolled persistence of their elevated biosynthetic functions are crucial determinants of the extent and rate of progression of the fibrotic process in systemic sclerosis.

The immunologic alterations include the production of numerous autoantibodies, some with very high specificity for the disease, as well as abnormalities in the innate and acquired cellular immune responses. [12, 13] The exaggerated connective tissue production by systemic sclerosis fibroblasts is induced by cytokines and growth factors released from the tissue-infiltrating inflammatory cells.

One of the growth factors that plays a crucial role in the fibrosis that accompanies systemic sclerosis is TGF-β. One of the most important effects of TGF-β is the stimulation of ECM synthesis by stimulating the production of various collagens and other ECM proteins. [10, 11] Besides its potent ECM stimulatory effects, TGF-β also induces the generation of myofibroblasts and decreases the production of collagen-degrading metalloproteinases. TGF-β also stimulates the production of protease inhibitors, which prevent ECM breakdown.

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