Soluble FLT1 sensitizes endothelial cells to inflammatory cytokines by antagonizing VEGF receptor-mediated signalling.
Soluble FLT1 sensitizes endothelial cells to inflammatory cytokines by antagonizing VEGF receptor-mediated signalling.
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DOI：
10.1093/cvr/cvq346
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发表时间：
2011-02-15
影响因子：
10.8
通讯作者：
Charnock-Jones DS
中科院分区：
文献类型：
--
作者：
Cindrova-Davies T;Sanders DA;Burton GJ;Charnock-Jones DS
先兆子痫影响5-7%的怀孕，是产妇和胎儿死亡的主要原因。胎盘来源的血管内皮生长因子（VEGF）受体剪接变体（可溶性fms样酪氨酸激酶-1（sFLT 1））的血清水平升高与发病机制密切相关，但尚未描述其潜在机制。过度的炎症样反应被认为是导致母体内皮细胞功能障碍的原因，而内皮细胞功能障碍是先兆子痫的特征。我们假设sFLT 1拮抗自分泌VEGF-A信号传导，使内皮细胞对胎盘释放的促炎因子更敏感。我们通过操纵VEGF受体信号传导和用低剂量肿瘤坏死因子-α（TNF-α）处理内皮细胞来测试这一点。单独应用重组sFLT 1不能激活人脐静脉内皮细胞（HUVECs）。然而，通过与重组sFLT 1、抗FLT 1、抗VEGF受体2（KDR）、抗VEGF-A、VEGF受体酪氨酸激酶抑制剂SU 5614预孵育或敲低FLT 1或KDR转录物来拮抗内皮VEGF-A和/或胎盘生长因子（PlGF）的自分泌作用，使细胞对低剂量TNF-α更敏感。每种治疗增加激活，如通过增加内皮细胞间粘附分子1（ICAM 1），血管细胞粘附分子1（VCAM 1），内皮素1（ET-1），血管性血友病因子（vWF），和白细胞粘附，并导致AKT Ser 473和内皮型一氧化氮合酶（eNOS）Ser 1177磷酸化减少。我们的数据描述了sFLT 1使内皮细胞对促炎因子敏感的机制，为胎盘应激如何导致先兆子痫综合征提供了解释。
Pre-eclampsia affects 5–7% of pregnancies, and is a major cause of maternal and foetal death. Elevated serum levels of placentally derived splice variants of the vascular endothelial growth factor (VEGF) receptor, soluble fms-like tyrosine kinase-1 (sFLT1), are strongly implicated in the pathogenesis but, as yet, no underlying mechanism has been described. An excessive inflammatory-like response is thought to contribute to the maternal endothelial cell dysfunction that characterizes pre-eclampsia. We hypothesized that sFLT1 antagonizes autocrine VEGF-A signalling, rendering endothelial cells more sensitive to pro-inflammatory factors also released by the placenta. We tested this by manipulating VEGF receptor signalling and treating endothelial cells with low doses of tumour necrosis factor-α (TNF-α). Application of recombinant sFLT1 alone did not activate human umbilical vein endothelial cells (HUVECs). However, antagonizing the autocrine actions of endothelial VEGF-A and/or placenta growth factor (PlGF) by pre-incubation with recombinant sFLT1, anti-FLT1, anti-VEGF receptor 2 (KDR), anti-VEGF-A, VEGF receptor tyrosine kinase inhibitor SU5614, or knocking-down FLT1 or KDR transcripts rendered cells more sensitive to low doses of TNF-α. Each treatment increased activation, as measured by increases in endothelial intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), endothelin 1 (ET-1), von Willebrand factor (vWF), and leucocyte adhesion, and led to reduction in AKT Ser473 and endothelial nitric oxide synthase (eNOS) Ser1177 phosphorylation. Our data describe a mechanism by which sFLT1 sensitizes endothelial cells to pro-inflammatory factors, providing an explanation for how placental stress may precipitate the pre-eclamptic syndrome.
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