Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy.
J Cell Mol Med. 2010 Jun;14(6A):1241-54. doi: 10.1111/j.1582-4934.2010.01027.x. Epub 2010 Jan 30.
Systemic sclerosis (SSc, scleroderma) is a chronic, multisystem connective tissue disorder affecting the skin and various internal organs. Although the disease is characterized by a triad of widespread microangiopathy, fibrosis and autoimmunity, increasing evidence indicates that vascular damage is a primary event in the pathogenesis of SSc. The progressive vascular injury includes persistent endothelial cell activation/damage and apoptosis, intimal thickening, delamination, vessel narrowing and obliteration. These profound vascular changes lead to vascular tone dysfunction and reduced capillary blood flow, with consequent tissue ischemia and severe clinical manifestations, such as digital ulceration or amputation, pulmonary arterial hypertension and scleroderma renal crisis. The resulting tissue hypoxia induces complex cellular and molecular mechanisms in the attempt to recover endothelial cell function and tissue perfusion. Nevertheless, in SSc patients there is no evidence of significant angiogenesis and the disease evolves towards chronic tissue ischemia, with progressive and irreversible structural changes in multiple vascular beds culminating in the loss of capillaries. A severe imbalance between pro-angiogenic and angiostatic factors may also lead to impaired angiogenic response during SSc. Besides insufficient angiogenesis, defective vasculogenesis with altered numbers and functional defects of bone marrow-derived endothelial progenitor cells may contribute to the vascular pathogenesis of SSc. The purpose of this article is to review the contribution of recent studies to the understanding of the complex mechanisms of impaired vascular repair in SSc. Indeed, understanding the pathophysiology of SSc-associated vascular disease may be the key in dissecting the disease pathogenesis and developing novel therapies. Either angiogenic or vasculogenic mechanisms may potentially become in the future the target of therapeutic strategies to promote capillary regeneration in SSc.
系统性硬化症（SSc，硬皮病）是一种慢性、多系统结缔组织疾病，影响皮肤和各种内脏器官。尽管该疾病的特征是广泛的微血管病变、纤维化和自身免疫的三联征，但越来越多的证据表明血管损伤是 SSc 发病机制中的一个主要事件。进行性血管损伤包括持续的内皮细胞激活/损伤和凋亡、内膜增厚、分层、血管狭窄和闭塞。这些深刻的血管变化导致血管张力功能障碍和毛细血管血流减少，从而导致组织缺血和严重的临床表现，如指溃疡或截肢、肺动脉高压和硬皮病肾危象。由此产生的组织缺氧在试图恢复内皮细胞功能和组织灌注时会引起复杂的细胞和分子机制。然而，在 SSc 患者中，没有证据表明有明显的血管生成，并且疾病会向慢性组织缺血发展，导致多个血管床的进行性和不可逆转的结构变化，最终导致毛细血管丧失。促血管生成和血管生成抑制因子之间的严重失衡也可能导致 SSc 期间血管生成反应受损。除了血管生成不足之外，骨髓源性内皮祖细胞数量和功能缺陷的血管生成缺陷也可能导致 SSc 的血管发病机制。本文的目的是回顾最近的研究对理解 SSc 中受损的血管修复复杂机制的贡献。事实上，了解 SSc 相关血管疾病的病理生理学可能是剖析疾病发病机制和开发新疗法的关键。血管生成或血管生成机制都可能成为未来促进 SSc 中毛细血管再生的治疗策略的靶点。
