How does endothelial cell injury start? The role of endothelin in systemic sclerosis

Abstract

A considerable amount of research time has been invested in studies aimed at elucidating pathogenic processes in systemic sclerosis (SSc). Despite this, major challenges for biomedical science remain, such as identification of the key factors that determine susceptibility to SSc, and elucidation of the precise nature of the initiating event that causes endothelial cell injury and ultimately brings about the biological cascade(s) that lead to the pathologic vascular changes. Involved factors are likely to include genetic perturbations, environmental cues, tissue injury, infection and hypoxia/oxidative stress. As important as determining the initiating events are the identification and characterization of key factors that are functionally important in driving vascular disease progression, because these factors are potential targets for therapeutic intervention. This article reviews the role of endothelin as an example of a pleiotropic mediator with effects on various aspects of SSc pathogenesis, such as inflammation, vasculopathy and tissue remodelling.

Figure 1

The myriad of potential consequences of endothelial dysfunction. Many human diseases, and in particular some of the most common diseases, are characterized by abnormal changes that take place within the blood vessel and alter vascular responses and function. vSMC, vascular smooth muscle cells.

Figure 2

Sequence of pathological events leading to the development of SSc. ECM, extracellular matrix; IL, interleukin; PDGF, platelet-derived growth factor; SMC, smooth muscle cell; SSc, systemic sclerosis; TGF, transforming growth factor.

Figure 3

Overview of ET-1 biosynthesis and function. Endothelial cell stimulation promotes the synthesis of pre-pro endothelin (ET)-1 polypeptides, the activation of processes that result in production of ET-1, and local release of mature ET-1. ET-1 interacts with specific endothelin receptors (endothelin receptor subtype A [ET_A] and ET_B) expressed on the surface of vascular smooth muscle cells and adventitial fibroblasts, and with ET_B receptors in endothelial cells. Recognition of ET-1 by these receptors activates intracellular signalling pathways and cascades that result in rapid alterations in cell activity and function, and initiates transcriptional programmes. Several points along the pathways of production, release, receptor ligation and signalling, as well as transcriptional activation, are potential targets for intervention. aa, amino acids; ERA, endothelin receptor antagonist; IL, interleukin; siRNA, small interfering RNA; SMC, smooth muscle cell; TGF, transforming growth factor.

Figure 4

Dual action of ET-1 on mesenchymal cell types. Shown are key activities of endothelin (ET)-1 on endothelial cells, vascular smooth muscle cells (vSMCs) and fibroblasts. Rapid endothelin-mediated responses include the modulation of calcium concentration and influx, levels of nitric oxide (NO) and cGMP, and the associated contractile response in order to regulate vascular tone. Slower more adaptive responses include the activation of transcriptional programmes to effect mesenchymal cell transition and differentiation, and extracellular matrix (ECM) production resulting in tissue remodelling. DAG, diacylglycerol; ET_A/BR, endothelin receptor subtype A/B receptor; IP₃, inositol trisphosphate; MAPK, mitogen-activated protein kinase; PIP, phosphatidylinositol phosphate; PKB, protein kinase B; PKC, protein kinase C; PLC, phospholipase C.