Abstract
Angiogenesis drives evolution and destabilisation of atherosclerotic plaques and the growth and expansion of tumour cells. Vascular endothelial growth factor (VEGF) is the main endogenous pro-angiogenic factor in humans. The aim was to provide insight into the anti-VEGF activity of bioactive compounds derived from aromatic amino acids (serotonin, melatonin, 3-indoleacetic acid, 5-hydroxytryptophol and hydroxytyrosol). Experiments involved endothelial cell migration (wound-healing assay), the molecular mechanisms (ELISA assay) and the downstream effects (phospholipase C gamma 1 (PLCγ1), protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) by Western blot) on human umbilical vein endothelial cells (HUVECs). The data suggest for the first time that hydroxytyrosol interacts with surface components of the endothelial cell membrane (, preventing VEGF from activating its receptor. Serotonin and 5-hydroxytryptophol significantly inhibited HUVEC migration (98% and 50%, respectively) following the same mechanism. Conversely to other bioactive compounds, the anti-angiogenic effect of melatonin, serotonin, 3-indoleacetic acid and 5-hydroxytryptophol is not mediated via PLCγ1. However, hydroxytyrosol inhibits PLCγ1 phosphorylation. Additionally, melatonin and serotonin maintained eNOS phosphorylation and hydroxytyrosol significantly activated eNOS—all via Akt. These data provide new evidence supporting the interest in melatonin, serotonin, 3-indoleacetic acid, 5-hydroxytryptophol and hydroxytyrosol for their further exploitation as anti-VEGF ingredients in food.
Highlights
Worldwide, cardiovascular diseases and cancer are the two main causes of death (31% and 16% of deaths in 2015, respectively) [1,2]
A number of polyphenol compounds usually synthesised in plant foods, such as epigallocatechin gallate (EGCG), quercetin or dp4 procyanidins, have been shown to directly inhibit the vascular endothelial growth factor (VEGF) molecule as an anti-angiogenic molecular mechanism [16]
Data are presented for the first time supporting that extra- and intra-cellular interactions between hydroxytyrosol and components of the cell surface (VEGFR-2, neurophilins, etc.)
Summary
Cardiovascular diseases and cancer are the two main causes of death (31% and 16% of deaths in 2015, respectively) [1,2]. Proof of the crucial function of VEGF in angiogenesis is the fact that certain drugs currently used to treat cancer, such as bevacizumab—the most widely used at present in treating breast, lung, kidney, liver and colon cancer—consist of anti-VEGF molecule treatment [12,13]. Their long-term use has been associated with serious adverse effects such as hypertension [14,15] due to the fact that
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