Pathogenesis of vasculopathy in systemic sclerosis and its contribution to fibrosis

Purpose of review In patients with systemic sclerosis (SSc), vascular manifestations precede skin and organ fibrosis. There is increasing evidence demonstrating a pathogenic link between early vascular injury and subsequent development of tissue fibrosis. Recent findings Our knowledge of cellular and molecular mechanisms underlying a unique relationship between SSc-related vasculopathy and fibrosis has changed over the last few years. There is increasing evidence showing viral infection as a potential trigger elucidating vascular injury. Due to defective vascular repair machinery, this initial event results in endothelial cell activation and apoptosis as well as the recruitment of inflammatory/immune cells, leading to endothelial-to-mesenchymal transition. This sequential process induces destructive vasculopathy in capillaries, fibroproliferative vascular lesions in arteries, and excessive fibrosis in the surrounding tissue. A variety of molecular mechanisms and pathways involved in vascular remodeling linked to subsequent excessive fibrosis have been identified and serve as attractive therapeutic targets for SSc. Summary Endothelial injury may play a central role in connecting three features that characterize SSc pathogenesis: vasculopathy, chronic inflammation, and fibrosis. Our understanding of the processes responsible for myofibroblast differentiation triggered by vascular injury will provide the rationale for novel targeted therapies for SSc.