Inhibition of VEGF-Induced VEGFR-2 Activation and HUVEC Migration by Melatonin and Other Bioactive Indolic Compounds.
Inhibition of VEGF-Induced VEGFR-2 Activation and HUVEC Migration by Melatonin and Other Bioactive Indolic Compounds.
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DOI：
10.3390/nu9030249
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发表时间：
2017-03-08
期刊：
影响因子：
5.9
通讯作者：
García-Parrilla MC
中科院分区：
文献类型：
--
作者：
Cerezo AB;Hornedo-Ortega R;Álvarez-Fernández MA;Troncoso AM;García-Parrilla MC
血管内皮生长因子(VEGF)浓度过高会触发血管生成，从而导致动脉粥样硬化斑块不稳定和肿瘤生长加速等并发症。本文主要研究褪黑素和其他吲哚类化合物对血管内皮生长因子受体-2(VEGFR-2)激活的抑制作用，并对其分子机制进行了初步探讨。用双抗体夹心法测定磷酸化VEGFR-2的含量。采用移行创面愈合实验测定人脐静脉内皮细胞(HUVECs)的迁移能力。这是褪黑素、3-吲哚乙酸、5-羟色酚和5-羟色胺首次被证实能显著抑制血管内皮生长因子诱导的人脐静脉内皮细胞VEGFR-2的激活和随后的血管生成。3-吲哚乙酸的抑制作用最强(IC50值为0.9704 mM)，其次是5-羟色酚(0.1 mM时抑制35%)、褪黑素(1 mM时抑制30%)和5-羟色胺(1 mM时抑制24%)。对这种抑制的分子机制提出了一个近似的观点，认为吲哚类化合物可能以一种阻止血管内皮生长因子激活受体的方式与内皮膜的细胞表面成分相互作用。此外，创伤愈合实验显示，在含有血管内皮细胞生长因子的情况下，褪黑素和3-吲哚乙酸对细胞迁移的抑制率分别为87%和99%，这表明褪黑素、3-吲哚乙酸、5-羟色酚和5-羟色胺是很有前景的抗血管内皮生长因子信号转导分子。
Excessive concentrations of vascular endothelial growth factor (VEGF) trigger angiogenesis, which causes complications such as the destabilization of atherosclerotic plaques and increased growth of tumors. This work focuses on the determination of the inhibitory activity of melatonin and other indolic related compounds on VEGF-induced VEGF receptor-2 (VEGFR-2) activation and an approximation to the molecular mechanism underlying the inhibition. Quantification of phosphorylated VEGFR-2 was measured by ELISA. Migration wound-healing assay was used to determine cell migration of human umbilical vein endothelial cells (HUVECs). This is the first time that melatonin, 3-indolacetic acid, 5-hydroxytryptophol, and serotonin are proved to significantly inhibit VEGF-induced VEGFR-2 activation in human umbilical vein endothelial cells and subsequent angiogenesis. 3-Indolacetic acid showed the highest inhibitory effect (IC50 value of 0.9704 mM), followed by 5-hydroxytryptophol (35% of inhibition at 0.1 mM), melatonin (30% of inhibition at 1 mM), and serotonin (24% of inhibition at 1 mM). An approximation to the molecular mechanism of the inhibition has been proposed, suggesting that indolic compounds might interact with the cell surface components of the endothelial membrane in a way that prevents VEGF from activating the receptor. Additionally, wound-healing assay revealed that exposure of HUVECs to melatonin and 3-indolacetic acid in the presence of VEGF significantly inhibited cell migration by 87% and 99%, respectively, after 24 h. These data demonstrate that melatonin, 3-indolacetic acid, 5-hydroxytryptophol, and serotonin would be good molecules for future exploitation as anti-VEGF signaling agents.