Vaccinium myrtillus (Bilberry) Extracts Reduce Angiogenesis In Vitro and In Vivo

Abstract

Vaccinium myrtillus (Bilberry) extracts (VME) were tested for effects on angiogenesis in vitro and in vivo. VME (0.3–30 µg ml−1) and GM6001 (0.1–100 µM; a matrix metalloproteinase inhibitor) concentration-dependently inhibited both tube formation and migration of human umbilical vein endothelial cells (HUVECs) induced by vascular endothelial growth factor-A (VEGF-A). In addition, VME inhibited VEGF-A-induced proliferation of HUVECs. VME inhibited VEGF-A-induced phosphorylations of extracellular signal-regulated kinase 1/2 (ERK 1/2) and serine/threonine protein kinase family protein kinase B (Akt), but not that of phospholipase Cγ (PLCγ). In an in vivo assay, intravitreal administration of VME inhibited the formation of neovascular tufts during oxygen-induced retinopathy in mice. Thus, VME inhibited angiogenesis both in vitro and in vivo, presumably by inhibiting the phosphorylations of ERK 1/2 and Akt. These findings indicate that VME may be effective against retinal diseases involving angiogenesis, providing it can reach the retina after its administration. Further investigations will be needed to clarify the major angiogenesis-modulating constituent(s) of VME.

Inhibitory actions of bilberry anthocyanidins on angiogenesis

“…After the medium exchange, anthocyanidins were capable of inhibiting VEGF-induced intracellular signaling within a few hours (before degradation of anthocyanidin). It was reported that VMA inhibits VEGF-induced activation of intracellular signaling, ERK1/2 (within 5 min) and Akt (within 10 min) (Matsunaga et al, 2007). It was considered that VMA can promptly inhibit the VEGFinduced signaling.…”

“…Recently, it was reported that VMA reduced both in vitro and in vivo angiogenesis (Matsunaga et al, 2007). Further, it was indicated that its effect may be due in part to reductions in cell proliferation and migration through inhibitions of both phosphorylated extracellular signal-regulated kinase 1/2 (ERK 1/2) and serine/ threonine protein kinase family protein kinase B (Akt) (Matsunaga et al, 2007).…”

“…Further, it was indicated that its effect may be due in part to reductions in cell proliferation and migration through inhibitions of both phosphorylated extracellular signal-regulated kinase 1/2 (ERK 1/2) and serine/ threonine protein kinase family protein kinase B (Akt) (Matsunaga et al, 2007). In addition, it was demonstrated that the main anthocyanidin constituents (delphinidin, cyanidin and malvidin) of VMA have inhibitory effects on lipid peroxidation and also neuroprotective effects (Matsunaga et al, 2008).…”

“…Previous studies have established that VMA have powerful antioxidant effects, and at least some constituents of VMA might be expected to inhibit angiogenesis via such effects (Nakajima et al, 2004;Matsunaga et al, 2007Matsunaga et al, , 2008. In previous studies it was indicated that bilberry inhibits H 2 O 2 -induced expression of VEGF from the keratinocyte via antioxidant effects (Roy et al, 2002;Bagchi et al, 2004).…”

Anthocyanins as Functional Food Factors— Chemistry, Nutrition and Health Promotion —

“…However, this anecdote itself is not evidence-based, and several clinical studies failed to verify the above claim (Levy and Glovinsky, 1998;Zadok et al, 1999;Muth et al, 2000; Canter and Ernst, 2004). On the other hand, bilberry anthocyanins have been shown to exhibit neuroprotective effects in ocular tissue and suppressive effects on diabetic retinopathy via a reduction of angiogenesis (Matsunaga et al, 2010a(Matsunaga et al, , 2010b. Furthermore, several studies have demonstrated that blackcurrant anthocyanins (BA) improve visual function; for example, BA inhibit transient myopia, reduce eye fatigue, improve dark adaptation, and increase retinal blood flow in glaucoma (Nakaishi et al, 2000;Ohguro et al, 2007; Iida et al, 2010).…”