Angiogenesis in Systemic Sclerosis Impaired Expression of Vascular Endothelial Growth Factor Receptor 1 in Endothelial Progenitor-Derived Cells Under Hypoxic Conditions
Angiogenesis in Systemic Sclerosis Impaired Expression of Vascular Endothelial Growth Factor Receptor 1 in Endothelial Progenitor-Derived Cells Under Hypoxic Conditions
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DOI：
10.1002/art.23968
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发表时间：
2008-11-01
影响因子：
--
通讯作者：
Allanore, Y.
中科院分区：
文献类型：
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作者：
Avouac, J.;Wipff, J.;Allanore, Y.
Objective.评估SSc患者和对照组的血管生成，并探讨血管内皮生长因子（VEGF）、VEGF受体1（VEGFR-1）和VEGFR-2（血管生成的主要介质）的表达和调节。在正常和缺氧条件下，对从系统性硬化症（SSc）患者和对照组外周血中分离的晚期生长内皮祖细胞（EPCs）和人脐静脉内皮细胞（HUVECs）进行了评估。在一项大型病例对照研究（包括659例SSc患者和511例对照）中，使用VEGFR 1和VEGFR 2基因标签单核苷酸多态性评估基因组背景。SSc患者的EPCs具有真正内皮细胞的表型，并显示出与基础条件下的HUVECs和对照EPCs相似的体外血管生成特性，如通过流式细胞术、管形成和迁移测定所确定的。然而，经过6小时的低氧暴露，SSc患者的EPCs表现出较低的诱导表达VEGFR-I的信使RNA和蛋白质水平，但类似的VEGF和VEGFR-2的表达，与HUVECs或健康对照组的EPCs。没有缺氧诱导因子1 α表达缺陷的证据。与健康对照组（n = 48）相比，SSc患者（n = 187）中可溶性VEGFR-1的血清水平较低（平均值+/- SD 163.7 +/- 98.5 vs 210.4 +/- 109.5 pg/ml; P = 0.0042），这支持了这些结果。这些异常似乎与基因组背景无关。我们的研究结果揭示了VEGFR-1在SSc中发生的主要血管紊乱中可能发挥的作用，并导致更严重的疾病。
Objective. To assess angiogenesis and explore the expression and regulation of vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR-1), and VEGFR-2, the leading mediators of angiogenesis, in SSc patients and controls.Methods. Late-outgrowth endothelial progenitor cells (EPCs), isolated from the peripheral blood of systemic sclerosis (SSc) patients and controls, and human umbilical vein endothelial cells (HUVECs) were assessed under normal and hypoxic conditions. Genomic background was evaluated in a large case-control study (including 659 patients with SSc and 511 controls) using tag single-nucleotide polymorphisms on VEGFR1 and VEGFR2 genes.Results. EPCs from SSc patients had the phenotype of genuine endothelial cells and displayed in vitro angiogenic properties similar to those of HUVECs and control EPCs under basal conditions, as determined by flow cytometry, tube formation, and migration assay. However, after 6 hours of hypoxic exposure, EPCs from SSc patients exhibited lower induced expression of VEGFR-I at the messenger RNA and protein levels, but similar VEGF and VEGFR-2 expression, compared with HUVECs or EPCs from healthy controls. There was no evidence of defective expression of hypoxia-inducible factor 1 alpha. These results were supported by the lower serum levels of soluble VEGFR-1 found in SSc patients (n = 187) compared with healthy controls (n = 48) (mean +/- SD 163.7 +/- 98.5 versus 210.4 +/- 109.5 pg/ml; P = 0.0042). These abnormalities did not seem to be related to genomic background.Conclusion. Our findings shed new light on the possible role of VEGFR-1 in the main vascular disturbances that occur in SSc and lead to more severe disease.