Cuadrado M J, Buendía P, Velasco F, Aguirre M A, Barbarroja N, Torres L A, Khamashta M, López-Pedrera C
Lupus Research Unit, St Thomas' Hospital, London, UK, and Research Unit and Rheumatology Department, Reina Sofía University Hospital, Cordoba, Spain.
J Thromb Haemost. 2006 Nov;4(11):2461-9. doi: 10.1111/j.1538-7836.2006.02193.x. Epub 2006 Sep 12.
One of the described mechanisms leading to thrombosis in antiphospholipid syndrome (APS) is overexpression of tissue factor (TF) in the monocytes and endothelial cells of patients with antiphospholipid antibodies (aPL). Vascular endothelial growth factor (VEGF) may stimulate monocyte TF expression through its receptor, the tyrosine kinase Flt-1.
This study aimed to analyze the following in monocytes of 55 primary APS patients: VEGF and Flt-1 expression levels, their potential regulation by aPL, and the association of VEGF and Flt-1 expression with the increased TF expression found in APS patients.
Purified monocytes from APS patients showed higher levels of VEGF and Flt-1 than healthy donors, which further correlated with immunoglobulin G (IgG) anticardiolipin titers and TF expression rank. Moreover, monocyte VEGF and Flt-1 levels were significantly higher in patients with than in patients without previous thrombosis. In vitro, IgG from APS patients increased monocyte VEGF and Flt-1 expression in a dose-dependent manner. VEGF and Flt-1 expression was significantly inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580; this suggests the involvement of this kinase in the aPL-induced VEGF and Flt-1 upregulation.
Our data show, for the first time in vivo, that monocytes from primary APS patients have an increased expression of VEGF and Flt-1. Furthermore, in vitro results indicated that this cytokine is produced by monocytes when treated with aPL, and that the p38 MAPK signaling pathway plays an important role. Thus, VEGF might act as a regulatory factor in aPL-mediated monocyte activation and TF expression, thereby contributing to the proinflammatory-prothrombotic phenotype of APS patients.
抗磷脂综合征（APS）中导致血栓形成的一种已描述机制是抗磷脂抗体（aPL）患者的单核细胞和内皮细胞中组织因子（TF）的过度表达。血管内皮生长因子（VEGF）可能通过其受体酪氨酸激酶Flt-1刺激单核细胞TF表达。
本研究旨在分析55例原发性APS患者单核细胞中的以下内容：VEGF和Flt-1表达水平、aPL对其的潜在调节作用，以及VEGF和Flt-1表达与APS患者中发现的TF表达增加之间的关联。
来自APS患者的纯化单核细胞显示VEGF和Flt-1水平高于健康供体，这进一步与免疫球蛋白G（IgG）抗心磷脂滴度和TF表达等级相关。此外，有既往血栓形成的患者单核细胞VEGF和Flt-1水平显著高于无既往血栓形成的患者。在体外，APS患者的IgG以剂量依赖方式增加单核细胞VEGF和Flt-1表达。p38丝裂原活化蛋白激酶（MAPK）抑制剂SB203580显著抑制VEGF和Flt-1表达；这表明该激酶参与了aPL诱导的VEGF和Flt-1上调。
我们的数据首次在体内表明，原发性APS患者的单核细胞VEGF和Flt-1表达增加。此外，体外结果表明，单核细胞在用aPL处理时会产生这种细胞因子，并且p38 MAPK信号通路起重要作用。因此，VEGF可能作为aPL介导的单核细胞活化和TF表达的调节因子，从而导致APS患者的促炎-促血栓形成表型。
