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

Posted Sep 11 2009 4:58pm

In order to understand the initiators of endothelial injury and how the ensuing vascular dysfunction contributes to the development of systemic sclerosis (SSc), it is necessary to consider the normal biology of the endothelium and of the myriad of biological molecules and biological functions under its control, and to assess which specific processes are dysregulated in disease.

In SSc, the vasculopathy is one of the earliest pathological events, characterized by endothelial cell activation and altered vascular tone. These pathological changes are accompanied by the presence of pro-inflammatory cytokines and angiogenic regulatory factors, and the loss of redox control, leading to oxidative stress and hypoxia.

This complex array of molecular interactions involves a number of cell types including the endothelial cells and their attendant perivascular supporting cells (pericytes and vascular smooth muscle cells [vSMCs]), and inflammatory cells, and they are profoundly influenced by the presence of growth factors, cytokines, chemokines and potent vasoactive factors.

Together, this diverse range of factors is believed to initiate and drive the vascular pathogenesis that leads to severe vessel disease and occlusion. Here we focus on one particularly attractive candidate, endothelin, and critically examine the cellular and molecular activities mediated by endothelin and its receptors that are intimately associated with endothelial cell injury and vascular dysfunction in SSc.

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.

Abraham and Distler Arthritis Research & Therapy 2007 9(Suppl 2):S2 doi:10.1186/ar2186

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