Mechanisms of Vascular Disease

Abundant evidence suggests that vascular endothelial injury is the initial trigger for the development of scleroderma (systemic sclerosis (SSc)). Prominent SSc vascular abnormalities are typically observed in the capillaries and the small blood vessels. In the capillaries, the vascular disease is characterized by distorted and irregular capillary loops in all involved anatomical districts. Capillary rarefaction (decreased capillary density) is seen particularly after the onset of tissue fibrosis. On the functional level, endothelial cells regulate vascular tone by producing vasoconstrictive and vasodilatory molecules. Vascular dysfunction can cause an imbalance favoring the production of vasoconstrictors and impaired vasodilatory pathway. Increased expression of adhesion molecules, platelet activation, and imbalance in coagulation/fibrinolysis axes result in microvascular thrombosis and enhanced fibrin deposition. Defective vascular repair and regeneration mechanisms and the endothelial-to-mesenchymal transition process appear to underlie the complexity of SSc-related microvasculopathy. Regression of SSc vascular disease has been difficult to achieve despite substantial symptomatic improvement through vascular-directed therapeutic approaches. In this chapter, we will review mechanisms of vascular disease in SSc and examine recent development in the field.