The role of endothelin in the pathogenesis of vasculopathy associated with systemic sclerosis

系统性硬化症（SSc）是一种多系统自身免疫性疾病，以初始血管损伤和皮肤及某些内脏纤维化为特征。尽管SSc的发病机制尚不清楚，但最近的研究表明，内皮素在与SSc相关的血管病变和纤维化的发展中起着至关重要的作用。一致地，我们最近发现Fli1缺乏与SSc中成纤维细胞和内皮细胞的激活密切相关，双内皮素受体拮抗剂波生坦通过增加Fli1的转录活性来逆转SSc真皮成纤维细胞的促纤维化表型。基于这些发现，我们在此研究了波生坦对SSc血管病变的影响，使用内皮细胞特异性Fli1敲除小鼠，模拟SSc血管病变的形态和功能异常。一系列研究表明，波生坦通过增加Fli1的转录活性来逆转这些小鼠的Fli1缺陷依赖性血管病变，这表明类似的机制可能支持波生坦治疗SSc血管病变的临床疗效。

Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by initial vascular injuries and resultant fibrosis of skin and certain internal organs. Although the pathogenesis of SSc still remains unknown, recent studies have demonstrated that endothelins play a crucial role in the development of vasculopathy and fibrosis associated with SSc. Consistently, we recently showed that Fli1 deficiency is closely linked to the activation of fibroblasts and endothelial cells in SSc and a dual endothelin receptor antagonist, bosentan, reverses the pro-fibrotic phenotype of SSc dermal fibroblasts by increasing the transcriptional activity of Fli1. Based on these findings, we herein investigated the impact of bosentan on SSc vasculopathy using endothelia cell-specific Fli1 knockout mice, which mimic the morphological and functional abnormalities of SSc vasculopathy. A series of studies revealed that bosentan reverses Fli1 deficiency-dependent vasculopathy in these mice by increasing transcriptional activity of Fli1, suggesting that a similar mechanism potentially underpins the clinical efficacy of bosentan for SSc vasculopathy.