Zaccone Vincenzo, Falsetti Lorenzo, Contegiacomo Silvia, Cataldi Serena, Benfaremo Devis, Moroncini Gianluca
PhD Course in Human Health, Marche Polytechnic University, 60126 Ancona, Italy.
Clinica Medica, Department of Clinical and Molecular Sciences, Marche Polytechnic University, 60126 Ancona, Italy.
Biomedicines. 2025 Jul 19;13(7):1771. doi: 10.3390/biomedicines13071771.
Systemic sclerosis (SSc) is a heterogeneous disease characterized by vascular alterations, immune dysregulation, and fibrosis. Solid evidence supports the hypothesis that endothelial dysfunction is the key player in SSc vascular injury and a critical factor concurring to the initiation of SSc pathogenesis. This narrative review reports on persistent endothelial dysfunction, resulting from oxidative stress, autoimmunity, and impaired vascular repair, in the course of SSc, and how it can trigger and sustain fibrotic remodeling of various organs. In this paper, we also analyze the impact on SSc of impaired angiogenesis and vasculogenesis, diminished endothelial progenitor cell function, and endothelial-to-mesenchymal transition, which can collectively disrupt vascular homeostasis and promote myofibroblast activation. These pathologic events underlie the hallmark clinical manifestations, i.e., Raynaud's phenomenon, digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. The review highlights how recognizing SSc as a paradigm of systemic endothelial dysfunction may reframe our understanding of its physiopathology, modify current therapeutic strategies, and unveil new therapeutic targets.
系统性硬化症（SSc）是一种异质性疾病，其特征为血管改变、免疫失调和纤维化。确凿证据支持以下假说：内皮功能障碍是SSc血管损伤的关键因素，也是促成SSc发病机制起始的关键因素。本叙述性综述报道了在SSc病程中，由氧化应激、自身免疫和血管修复受损导致的持续性内皮功能障碍，以及它如何引发和维持各器官的纤维化重塑。在本文中，我们还分析了血管生成和血管发生受损、内皮祖细胞功能减退以及内皮向间充质转化对SSc的影响，这些因素共同作用可破坏血管稳态并促进肌成纤维细胞活化。这些病理事件是标志性临床表现的基础，即雷诺现象、指端溃疡、肺动脉高压和硬皮病肾危象。该综述强调，将SSc视为系统性内皮功能障碍的范例，可能会重塑我们对其生理病理学的理解，修改当前的治疗策略，并揭示新的治疗靶点。
