Differential regulation of diverse physiological responses to VEGF in pulmonary endothelial cells
Differential regulation of diverse physiological responses to VEGF in pulmonary endothelial cells
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DOI：
10.1152/ajplung.2001.281.6.l1500
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发表时间：
2001-12-01
影响因子：
4.9
通讯作者：
Garcia, JGN
中科院分区：
文献类型：
--
作者：
Becker, PM;Verin, AD;Garcia, JGN
血管内皮细胞对血管内皮生长因子(VEGF)的不同生理反应机制尚不完全清楚。我们假设，血管内皮细胞生长因子通过细胞内信号转导通路的不同激活而引起内皮通透性增加和细胞迁移。为了验证这一假设，我们用牛肺内皮细胞建立了血管内皮生长因子诱导的内皮屏障功能障碍和趋化作用的模型。我们比较了血管内皮生长因子对肺内皮细胞跨内皮细胞电阻(TER)、肌动蛋白细胞骨架重塑和趋化作用的影响，并评价了丝裂原活化蛋白激酶(MAPKs)p38和细胞外信号调节激酶(ERK)1/2在血管内皮细胞介导的血管内皮细胞反应中的作用。在评价屏障调节和趋化作用时，肺微血管内皮细胞和肺动脉微血管内皮细胞对血管内皮生长因子的剂量反应不同。抑制酪氨酸激酶、磷酸肌醇3-激酶或p38MAPK可显著减弱血管内皮生长因子介导的TER、F-肌动蛋白重塑和趋化作用。抑制ERK1/2MAPK，但不抑制胎肝激酶-1(Flk-1)或Src激酶，也可显著减弱VEGF介导的TER下降。相反，血管内皮细胞生长因子介导的内皮迁移不能被ERK1/2抑制减弱，但可被Flk-1或Src激酶抑制而被取消。这些数据表明，在体内，血管内皮生长因子可能通过不同的方式调节生理反应。
The mechanisms responsible for the divergent physiological responses of endothelial cells to vascular endothelial growth factor (VEGF) are incompletely understood. We hypothesized that VEGF elicits increased endothelial permeability and cell migration via differential activation of intracellular signal transduction pathways. To test this hypothesis, we established a model of VEGF-induced endothelial barrier dysfunction and chemotaxis with bovine pulmonary endothelial cells. We compared the effects of VEGF on transendothelial electrical resistance (TER), actin cytoskeletal remodeling, and chemotaxis of lung endothelial cells and then evaluated the role of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK)1/2 in VEGF-mediated endothelial responses. The dose response of pulmonary arterial and lung microvascular endothelial cells to VEGF differed when barrier regulation and chemotaxis were evaluated. Inhibition of tyrosine kinase, phosphoinositol 3-kinase, or p38 MAPK significantly attenuated VEGF-mediated TER, F-actin remodeling, and chemotaxis. VEGF-mediated decreased TER was also significantly attenuated by inhibition of ERK1/2 MAPK but not by inhibition of fetal liver kinase-1 (flk-1) or Src kinase. In contrast, VEGF-mediated endothelial migration was not attenuated by ERK1/2 inhibition but was abolished by inhibition of either flk-1 or Src kinase. These data suggest potential mechanisms by which VEGF may differentially mediate physiological responses in vivo.