Kuwana Masataka, Okazaki Yuka, Yasuoka Hidekata, Kawakami Yutaka, Ikeda Yasuo
Institute for Advanced Medical Research Keio University School of Medicine, Tokyo, Japan.
Lancet. 2004;364(9434):603-10. doi: 10.1016/S0140-6736(04)16853-0.
Typical vascular features of systemic sclerosis include low capillary density and vascular obliteration. The formation and repair of blood vessels in adults involve vasculogenesis, which is mediated through the recruitment of bone-marrow-derived circulating endothelial precursors (CEP). We investigated whether vasculogenesis is impaired in patients with systemic sclerosis.
Peripheral blood was obtained from 11 patients with systemic sclerosis, 11 with rheumatoid arthritis, and 11 healthy controls. Factors potentially affecting the CEP number were matched among the three groups. CEP (identified as circulating cells positive for CD34, CD133, and the type 2 receptor for vascular endothelial growth factor) were quantified by cell sorting and three-colour flow cytometry. The circulating concentrations of angiogenic factors were measured by ELISA. The potential of CEP to differentiate into endothelial cells was assessed by the upregulation of von Willebrand factor after in-vitro maturation treatment. Findings The absolute number of CEP was much lower in patients with systemic sclerosis than in patients with rheumatoid arthritis or healthy controls (median 274 [IQR 178-395] vs 1154 [653-1524] and 1074 [713-1186] per 20 mL peripheral blood, respectively; p<0.0001 by Kruskal-Wallis test. Paradoxically, circulating concentrations of most angiogenic factors were significantly higher in patients with systemic sclerosis than in healthy controls. The proportion of CEP that differentiated into endothelial cells was significantly lower in patients with systemic sclerosis than in healthy controls (p<0.0001, Mann-Whitney test).
Insufficient vascular repair machinery due to defective vasculogenesis might contribute to vasculopathy in systemic sclerosis.
As well as providing an important insight into the pathogenesis of this disorder, these findings suggest that dysregulated vasculogenesis might be important in other disorders with abnormalities in vascular formation, including those with excessive formation of new vessels such as cancer and those with deficient vessel formation such as atherosclerosis. Circulating endothelial precursors could be a novel target for therapeutic strategies for ischaemic complications in patients with systemic sclerosis.
系统性硬化症的典型血管特征包括毛细血管密度降低和血管闭塞。成人血管的形成和修复涉及血管生成，这是通过募集骨髓来源的循环内皮前体细胞（CEP）介导的。我们研究了系统性硬化症患者的血管生成是否受损。
从11例系统性硬化症患者、11例类风湿关节炎患者和11名健康对照者中获取外周血。在三组中匹配可能影响CEP数量的因素。通过细胞分选和三色流式细胞术对CEP（鉴定为CD34、CD133和血管内皮生长因子2型受体阳性的循环细胞）进行定量。通过ELISA测量血管生成因子的循环浓度。通过体外成熟处理后血管性血友病因子的上调来评估CEP分化为内皮细胞的潜力。
系统性硬化症患者的CEP绝对数量远低于类风湿关节炎患者或健康对照者（每20 mL外周血中位数分别为274 [四分位间距178 - 395] vs 1154 [653 - 1524]和1074 [713 - 1186]；Kruskal - Wallis检验p<0.0001）。矛盾的是，系统性硬化症患者中大多数血管生成因子的循环浓度显著高于健康对照者。系统性硬化症患者中分化为内皮细胞的CEP比例显著低于健康对照者（p<0.0001，Mann - Whitney检验）。
血管生成缺陷导致的血管修复机制不足可能导致系统性硬化症中的血管病变。
这些发现不仅为该疾病的发病机制提供了重要见解，还表明血管生成失调在其他血管形成异常的疾病中可能很重要，包括那些新血管过度形成的疾病如癌症以及那些血管形成不足的疾病如动脉粥样硬化。循环内皮前体细胞可能是系统性硬化症患者缺血性并发症治疗策略中的一个新靶点。
