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eCAM Advance Access published online on October 27, 2007
eCAM, doi:10.1093/ecam/nem151
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© 2007 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Nozomu Matsunaga1, Yuichi Chikaraishi1, Masamitsu Shimazawa1, Shigeru Yokota2 and Hideaki Hara1

1Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585 and 2Wakasa Seikatsu Co. Ltd, 22 Naginataboko-cho, Shijo-Karasuma, Shimogyo-ku, Kyoto 600-8008, Japan

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 C{gamma} (PLC{gamma}). 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.

Keywords: angiogenesis – VEGF – Bilberry (Vaccinium myrtillus) extraction – GM6001 – MMP – antioxidant – ERK 1/2 – PLC{gamma} – Akt

For reprints and all correspondence: Professor H. Hara, PhD, Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585. Japan. Tel: +81-58-237-8596; Fax: +81-58-237-8596; E-mail: hidehara{at}gifu-pu.ac.jp

Received February 6, 2007; accepted September 12, 2007


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