Fleming Jo N, Nash Richard A, McLeod D O, Fiorentino David F, Shulman Howard M, Connolly M Kari, Molitor Jerry A, Henstorf Gretchen, Lafyatis Robert, Pritchard David K, Adams Lawrence D, Furst Daniel E, Schwartz Stephen M
Department of Pathology, University of Washington, Seattle, Washington, United States of America.
PLoS One. 2008 Jan 16;3(1):e1452. doi: 10.1371/journal.pone.0001452.
Scleroderma is an autoimmune disease with a characteristic vascular pathology. The vasculopathy associated with scleroderma is one of the major contributors to the clinical manifestations of the disease.
METHODOLOGY/PRINCIPAL FINDINGS: We used immunohistochemical and mRNA in situ hybridization techniques to characterize this vasculopathy and showed with morphometry that scleroderma has true capillary rarefaction. We compared skin biopsies from 23 scleroderma patients and 24 normal controls and 7 scleroderma patients who had undergone high dose immunosuppressive therapy followed by autologous hematopoietic cell transplant. Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels. The molecules defining this phenotype are: vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation (lost in the scleroderma tissue), antiangiogenic interferon alpha (overexpressed in the scleroderma dermis) and RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis (also overexpressed in scleroderma skin. Following high dose immunosuppressive therapy, patients experienced clinical improvement and 5 of the 7 patients with scleroderma had increased capillary counts. It was also observed in the same 5 patients, that the interferon alpha and vascular endothelial cadherin had returned to normal as other clinical signs in the skin regressed, and in all 7 patients, RGS5 had returned to normal.
CONCLUSION/SIGNIFICANCE: These data provide the first objective evidence for loss of vessels in scleroderma and show that this phenomenon is reversible. Coordinate changes in expression of three molecules already implicated in angiogenesis or anti-angiogenesis suggest that control of expression of these three molecules may be the underlying mechanism for at least the vascular component of this disease. Since rarefaction has been little studied, these data may have implications for other diseases characterized by loss of capillaries including hypertension, congestive heart failure and scar formation.
硬皮病是一种具有特征性血管病变的自身免疫性疾病。与硬皮病相关的血管病变是该疾病临床表现的主要促成因素之一。
方法/主要发现：我们使用免疫组织化学和mRNA原位杂交技术来表征这种血管病变，并通过形态计量学表明硬皮病存在真正的毛细血管稀疏。我们比较了23例硬皮病患者、24例正常对照以及7例接受高剂量免疫抑制治疗后进行自体造血细胞移植的硬皮病患者的皮肤活检样本。随着毛细血管的丧失，残余血管中的内皮细胞表型发生了显著变化。定义这种表型的分子有：血管内皮钙黏蛋白，一种据推测是形成血管所需的通用内皮标志物（在硬皮病组织中缺失）；抗血管生成的α干扰素（在硬皮病真皮中过度表达）；以及RGS5，一种信号分子，其表达与发育和肿瘤血管生成过程中分支形态发生的结束相一致（在硬皮病皮肤中也过度表达）。高剂量免疫抑制治疗后，患者临床症状改善，7例硬皮病患者中有5例毛细血管计数增加。在这5例患者中还观察到，随着皮肤其他临床体征消退，α干扰素和血管内皮钙黏蛋白恢复正常，并且在所有7例患者中，RGS5也恢复正常。
结论/意义：这些数据为硬皮病中血管丧失提供了首个客观证据，并表明这种现象是可逆的。三种已涉及血管生成或抗血管生成的分子表达的协同变化表明，控制这三种分子的表达可能是该疾病至少血管部分的潜在机制。由于对毛细血管稀疏的研究较少，这些数据可能对包括高血压、充血性心力衰竭和瘢痕形成在内的其他以毛细血管丧失为特征的疾病具有启示意义。
