Vascular endothelial growth factor (VEGF)-D and VEGF-A differentially regulate KDR-mediated signaling and biological function in vascular endothelial cells
Vascular endothelial growth factor (VEGF)-D and VEGF-A differentially regulate KDR-mediated signaling and biological function in vascular endothelial cells
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DOI：
10.1074/jbc.m401538200
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发表时间：
2004-08-20
影响因子：
4.8
通讯作者：
Zachary, I
中科院分区：
文献类型：
--
作者：
Jia, HY;Bagherzadeh, A;Zachary, I
血管内皮生长因子（VEGF）-D与VEGF受体（VEGFR）VEGFR 2/KDR和VEGFR 3/Flt 4结合，但对介导其在内皮细胞中的生物活性的信号传导机制知之甚少。我们研究了VEGF-D的作用机制，并比较了VEGF-D和VEGF-A在内皮细胞中诱导的信号通路和生物学反应。VEGF-D诱导KDR和磷脂酶C-γ酪氨酸磷酸化的速度更慢，在早期比VEGF-A更有效，但效果更持久，60分钟后与VEGF-A一样有效。VEGF-D激活细胞外信号调节蛋白激酶1和2的效果相似，但与VEGF-A相比动力学较慢，这种作用可被蛋白激酶C和丝裂原活化蛋白激酶激酶抑制剂阻断。与VEGF-A相比，VEGF-D微弱地刺激前列环素的产生和基因表达，对细胞增殖几乎没有影响，并且刺激细胞内[Ca（2+）]的较小且更短暂的增加。VEGF-D诱导的磷脂酰肌醇3-激酶（PI 3 K）介导的Akt激活较强，但更短暂，增加PI 3 K依赖的内皮一氧化氮合酶磷酸化和细胞存活较弱。VEGF-D通过PI 3 K/Akt和内皮一氧化氮合酶依赖性途径刺激趋化性，增强蛋白激酶C和PI 3 K依赖性内皮小管形成，并在小鼠海绵植入模型中刺激血管生成，其效果低于VEGF-A。VEGF-D诱导的信号传导和生物学效应被KDR抑制剂SU 5614阻断。通过VEGF-A和VEGF-D的差异KDR活化对内皮信号传导和功能具有不同后果的发现对于理解相同VEGF受体的多个配体如何产生配体特异性生物反应具有重要意义。
Vascular endothelial growth factor (VEGF)-D binds to VEGF receptors (VEGFR) VEGFR2/KDR and VEGFR3/Flt4, but the signaling mechanisms mediating its biological activities in endothelial cells are poorly understood. Here we investigated the mechanism of action of VEGF-D, and we compared the signaling pathways and biological responses induced by VEGF-D and VEGF-A in endothelial cells. VEGF-D induced KDR and phospholipase C-gamma tyrosine phosphorylation more slowly and less effectively than VEGF-A at early times but had a more sustained effect and was as effective as VEGF-A after 60 min. VEGF-D activated extracellular signal-regulated protein kinases 1 and 2 with similar efficacy but slower kinetics compared with VEGF-A, and this effect was blocked by inhibitors of protein kinase C and mitogen-activated protein kinase kinase. In contrast to VEGF-A, VEGF-D weakly stimulated prostacyclin production and gene expression, had little effect on cell proliferation, and stimulated a smaller and more transient increase in intracellular [Ca(2+)]. VEGF-D induced strong but more transient phosphatidylinositol 3-kinase (PI3K)-mediated Akt activation and increased PI3K-dependent endothelial nitric-oxide synthase phosphorylation and cell survival more weakly. VEGF-D stimulated chemotaxis via a PI3K/Akt- and endothelial nitric-oxide synthase-dependent pathway, enhanced protein kinase C- and PI3K-dependent endothelial tubulogenesis, and stimulated angiogenesis in a mouse sponge implant model less effectively than VEGF-A. VEGF-D-induced signaling and biological effects were blocked by the KDR inhibitor SU5614. The finding that differential KDR activation by VEGF-A and VEGF-D has distinct consequences for endothelial signaling and function has important implications for understanding how multiple ligands for the same VEGF receptors can generate ligand-specific biological responses.