Antiangiogenic Activity of Acer tegmentosum Maxim Water Extract in Vitro and in Vivo

Angiogenesis, the formation of new blood vessels, is critical for tumor growth and metastasis. Notably, tumors themselves can lead to angiogenesis by inducing vascular endothelial growth factor (VEGF), which is one of the most potent angiogenic factors. Inhibition of angiogenesis is currently perceived as one of the most promising strategies for the blockage of tumor growth. In this study, we investigated the effects of Acer tegmentosum maxim water extract (ATME) on angiogenesis and its underlying signal mechanism. We studied the antiangiogenic activity of ATME by using human umbilical vein endothelial cells (HUVECs). ATME strongly inhibited VEGF-induced endothelial cell proliferation, migration, invasion, and tube formation, as well as vessel sprouting in a rat aortic ring sprouting assay. Moreover, we found that the p44/42 mitogen activated protein (MAP) kinase signaling pathway is involved in the inhibition of angiogenesis by ATME. Moreover, when we performed the in vivo matrigel plug assay, VEGF-induced angiogenesis was potently reduced when compared to that for the control group. Taken together, these results suggest that ATME exhibits potent antiangiogenic activity in vivo and in vitro and that these effects are regulated by the extracellular regulated kinase (ERK) pathway. Graphical Abstract Keywords: Angiogenesis, Acer tegmentosum Maxim, Vascular Endothelial Growth Factor A, p44/42 MAP Kinase INTRODUCTION Angiogenesis, the process of generating new microvascular networks, plays an important role in a wide range of physiological and pathological conditions, including embryonic development, wound healing, tissue regeneration, and tumor growth (1, 2, 3). Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic factors known to date (4, 5); it is secreted by a variety of cell types for functions such as regulating angiogenesis and tumor metastasis (6, 7, 8). Clinical studies of colorectal cancer have shown that the VEGF monoclonal antibody, bevacizumab, in combination with cytotoxic therapy positively affects patient survival rates (9). The VEGF-receptor (VEGF-R) tyrosine kinase inhibitor, vatalanib, has also shown to have an antitumorigenic effect in colorectal cancer as a result of antiangiogenic activity (9). Many herbs and their natural products are traditionally used in anticancer treatments and are known to exhibit antiangiogenic properties through various interdependent processes (10). Grape seed proanthocyanidins inhibit angiogenesis (11), and Gleditsia sinensis thorn extract has been shown to prevent colon cancer and angiogenesis both in vitro and vivo (12, 13). Acer tegmentosum (Acereaceae) has been used in Korean traditional medicine for the treatment of hepatic disorders (14). Diarylheptanoids (15), rhododendrol glycoside (16), and tannins (17) have been found in and isolated from the genus Acer. Compounds from the Acer tegmentosum Maxim methanol extract has been shown to be cytotoxic to cancer cell lines (18); however, no studies have examined its effect on angiogenesis or the underlying mechanisms. In this study, we investigated the effects of the A. tegmentosum maxim water extract (ATME) on angiogenesis and its underlying signal mechanism and found that the extract exhibits antiangiogenic potential both in vitro and in vivo.