Melatonin promotes angiogenesis during protection and healing of indomethacin-induced gastric ulcer: role of matrix metaloproteinase-2

Abstract

Matrix metalloproteinase (MMP)-2 is considered as a crucial regulator of angiogenesis, a process of new blood vessel formation. We reported previously that melatonin (N-acetyl-5-methoxy tryptamine), an antioxidant and anti-inflammatory agent, prevents indomethacin-induced gastric ulcers. Herein, we investigated the effect of melatonin on MMP-2-mediated angiogenesis during gastroprotection. Angiogenic properties of melatonin were tested in both rat corneal micropocket assay and in mouse model of indomethacin-induced gastric lesions. Melatonin augmented angiogenesis that was associated with amelioration of MMP-2 expression and activity and, upregulation of vascular endothelial growth factor (VEGF) in rat cornea. Melatonin prevented gastric lesions by promoting angiogenesis via upregulation of VEGF followed by over-expression of MMP-2. Similarly, healing of gastric lesions was associated with early expression of VEGF followed by MMP-2. In addition, upregulation of MMP-2 was parallel to MMP-14 and inverse to tissue inhibitor of metalloprotease (TIMP)-2 expression during gastroprotection. Our data demonstrated that melatonin exerts angiogenesis through MMP-2 and VEGF over-expression during protection and healing of gastric ulcers. This study highlights for the first time a phase-associated regulation of MMP-2 activity in gastric mucosa and an angiogenic action of melatonin to rescue indomethacin-induced gastropathy.

Curcumin Heals Indomethacin-Induced Gastric Ulceration by Stimulation of Angiogenesis and Restitution of Collagen FibersviaVEGF and MMP-2 Mediated Signaling

“…A combination of antioxidants (proanthocyanidin and resveratrol) from grapeseed has also been shown to increase VEGF expression and angiogenesis (13). Furthermore, we recently reported that melatonin, a pineal hormone, promotes MMP-2-mediated angiogenesis during healing of indomethacin-induced gastric ulceration (6).…”

“…1I). Various findings have shown that VEGFmediated MMP-2 signaling is essential for gastroprotection (6,25,30). Therefore, we examined VEGF and MMP-2 localization in gastric tissues using immunofluorescence ( Fig.…”

“…Transforming growth factor (TGF)-b accelerates angiogenesis by inducing matrix metalloproteinase (MMP) expression. MMPs degrade the basement membrane, extracellular matrix (ECM), and other ECM components during gastric ulcer formation (4,6,15,18,22,25,28,31,34). However, MMPs pro-…”

Melatonin as an Anti-angiogenetic, Immunomodulatory and Antitumoral Agent

“…Melatonin shielded from gastric lesions by upraising angiogenesis thru upregulation of VEGF accompanied with the support of over-expression of MMP-2. It showed that melatonin exerts angiogenesis thru MMP-2 and VEGF over-expression all through safety and recuperation of gastric ulcers [11].…”

Prevention of Gastric Ulcers

“…Organoselenium compounds were tested in naproxen-and Helicobacter pylori-induced gastric ulcers and showed not only gastro-protective and ulcer healing effects, but also they possessed antibacterial effect against Helicobacter pylori (Santhosh et al, 2010). When tested on indomethacin-induced gastric ulcer in mice, melatonin demonstrated gastro-protective effects via having angiogenic properties through up-regulation of matrix metalloproteinase-2; an important regulator of angiogenesis (Ganguly et al, 2010). The need for more effective and cheaper management and prevention of gastric ulcer has attracted an increasing interest for herbal products because of their effectiveness, less side effects and relatively low costs (Fig.…”