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. 1. Introduction Scleroderma or Systemic Sclerosis (SSc) is an autoimmune disease of unknown etiology characterized by progressive fibrosis of skin and multiple internal organs and prominent and often severe alterations in the microvasculature [1]. Although SSc is the third most common systemic inflammatory autoimmune disease and has the highest case-specific mortality among this group of idiopathic disorders, there is currently no effective disease-modifying therapy for SSc. Therefore, there is an urgent unmet need for the development of effective disease-modifying therapies to improve the devastating health consequences and high mortality caused by the disease. The cells responsible for the severe fibroproliferative process in SSc are activated myofibroblasts, a unique population of mesenchymal cells displaying unique biological functions including increased production of fibrillar type l and type lll collagens, initiation of expression of α-smooth muscle actin (α-SMA), a molecular marker of activated myofibroblasts, and reduction in the expression of genes encoding extracellular matrix (ECM)-degradative enzymes. The accumulation of myofibroblasts in
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