New mechanism-based approaches to treating and evaluating the vasculopathy of scleroderma.

Abstract

Utilizing recent insight into the vasculopathy of scleroderma (SSc), the review will highlight new opportunities for evaluating and treating the disease by promoting stabilization and protection of the microvasculature. Endothelial junctional signaling initiated by vascular endothelial-cadherin (VE-cadherin) and Tie2 receptors, which are fundamental to promoting vascular health and stability, are disrupted in SSc. This would be expected to not only diminish their protective activity, but also increase pathological processes that are normally restrained by these signaling mediators, resulting in pathological changes in vascular function and structure. Indeed, key features of SSc vasculopathy, from the earliest signs of edema and puffy fingers to pathological disruption of hemodynamics, nutritional blood flow, capillary structure and angiogenesis are all consistent with this altered endothelial signaling. It also likely contributes to further progression of the disease including tissue fibrosis, and organ and tissue injury. Restoring protective endothelial junctional signaling should combat the vasculopathy of SSc and prevent further deterioration in vascular and organ function. Indeed, this type of targeted approach has achieved remarkable results in preclinical models for other diseases. Furthermore, tracking this endothelial junctional signaling, for example by assessing vascular permeability, should facilitate insight into disease progression and its response to therapy.