Potential beneficial role for endothelin in scleroderma vasculopathy: inhibition of endothelial apoptosis by type B endothelin-receptor signaling

Abstract

Objectives Microvascular endothelial cell (MVEC) apoptosis is considered to be a key event in the pathogenesis of systemic sclerosis (SSc), an increased expression of endothelin-1 (ET1) is also well recognized in the disease. ET1 is thought to exert deleterious effects on the vasculature by virtue of its known vasospastic, proliferative and fibrotic effects, yet ET1 can act as a survival factor for a variety of cells, including MVEC. The aim of this study is to investigate if ET1 signaling protects SSc-MVECs from apoptosis. Methods The expression levels of ET1-receptor genes: Endothelin Receptor Type A gene (EDNRA) and Endothelin Receptor Type B gene (EDNRB), and the effects of selective Endothelin Receptor Type A (ETA) antagonists, selective Endothelin Receptor Type B (ETB), and dual ETA/B antagonist in the presence and/or absence of ET1 on control and SSc-MVEC apoptosis were examined. Results Significant increase in the expression of ETA and ETB was noted in SSc-MVECs. Growth factors withdrawal (GFW) resulted in a significant apoptosis that was considerably reduced by the addition ET1. The addition of ETA-receptor antagonists did not affect ET1 anti-apoptotic effects, while the nonselective ETA/B or the selective ETB-receptor antagonists blocked the anti-apoptotic effects of ET1. Finally, an upregulation of the proapoptotic gene BAX after GFW was noted that was normalized by the addition of ET1. Conclusions The results suggest that ET1 mediates an anti-apoptotic effect through engaging the ETB receptors in MVECs. Therefore, it appears that selective ETA antagonism may have an advantage over the non-selective ET1-receptor antagonists in SSc vasculopathy, particularly in the early stages of the disease when MVEC apoptosis is rampant.