Vasculopathy in scleroderma

Systemic sclerosis (SSc) is a multisystem connective tissue disorder featured by vascular injury and fibrosis of the skin and various internal organs with autoimmune background. Although the pathogenesis of SSc still remains elusive, it is generally accepted that initial vascular injury due to autoimmunity and/or environmental factors causes structural and functional abnormalities of vasculature which eventually result in the constitutive activation of fibroblasts in various organs. Structural alterations consist of destructive vasculopathy (loss of small vessels) and proliferative obliterative vasculopathy (occlusion of arterioles and small arteries with fibro-proliferative change) caused by impaired compensatory vasculogenesis and angiogenesis. Impaired function of SSc vasculature includes the altered expression of cell adhesion molecules predominantly inducing Th2 and Th17 cell infiltration, endothelial dysfunction primarily due to the low availability of nitric oxide, the activated endothelial-to-mesenchymal transition leading to fibro-proliferative vascular change and tissue fibrosis, and the impaired coagulation/fibrinolysis system promoting the formation of intravascular fibrin deposits. Recent new insights into the therapeutic mechanisms of intravenous cyclophosphamide pulse and bosentan and the establishment of a new SSc animal model (Klf5 (+/-);Fli1 (+/-) mice) provide us useful clues to further understand the development of vascular alterations characteristic of SSc. This article overviewed the present understanding of the pathogenesis of SSc vasculopathy.