Abstract
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.
Highlights
Angiogenesis, the physiological process in which new blood vessels are formed from pre-existing ones, plays a critical role on tumor progression and development, as well as in the development and destabilization of atherosclerotic plaques [1,2]
We proved that melatonin and 3-indolacetic acid inhibited human umbilical vein endothelial cells (HUVECs) cell migration in the anti‐angiogenic mechanism of of thethe action of melatonin and other indolic compounds on presence of Vascular endothelial growth factor (VEGF)
The data presented in this study show the potential for melatonin and its derivatives to inhibit VEGF receptor 2 (VEGFR-2) activation in vitro, the effects are likely to be undetectable in vivo after the consumption of melatonin-rich food
Summary
Angiogenesis, the physiological process in which new blood vessels are formed from pre-existing ones, plays a critical role on tumor progression and development, as well as in the development and destabilization of atherosclerotic plaques [1,2]. Vascular endothelial growth factor (VEGF) is the most active endogenous pro-angiogenic factor in humans [3,4,5,6]. VEGF triggers angiogenesis by binding to type III receptor tyrosine kinases on the cell surface, which causes the receptors to dimerize and become activated through transphosphorylation. VEGF receptor 2 (VEGFR-2) is the main mediator of the proliferation, migration, survival and permeability enhancing effect of VEGF [3,7,8]. These VEGF responses can be further promoted by a small number of VEGFR-2 co-receptors such as Nutrients 2017, 9, 249; doi:10.3390/nu9030249 www.mdpi.com/journal/nutrients
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