title: Esculetin Inhibits VEGF-Induced Angiogenesis Both In Vitro and In Vivo.
abstract: Esculetin is known to inhibit tumor growth, but its effect in angiogenesis has not been studied. Here, we report the efficacy of esculetin on VEGF-induced angiogenesis. Esculetin treatment inhibited VEGF-induced proliferation and DNA synthesis of HUVECs with no cell toxicity. G1-phase cell-cycle arrest was associated with a decreased expression of cyclins and CDKs via the binding of p27KIP1. Esculetin down-regulated the MMP-2 expression in VEGF-stimulated HUVECs, which suppressed colony tube formation and migration. Esculetin reduced the phosphorylation of VEGFR-2 and the downstream signaling of VEGFR-2, including ERK1/2 and eNOS/Akt pathways. Esculetin suppressed microvessel outgrowth from an aortic ring ex vivo model treated with VEGF, and blocked the VEGF-induced formation of new blood vessels and hemoglobin content in an in vivo Matrigel plug model. Collectively, VEGF-stimulated responses in angiogenesis were inhibited in vitro and in vivo, providing a theoretical basis for effective use against anti-angiogenic therapies.
authors.affiliation: * Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Republic of Korea.
authors.forename: Sung Lyea
authors.initials: SL
authors.lastname: Park
authors.affiliation: * Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Republic of Korea.
authors.forename: Se Yeon
authors.initials: SY
authors.lastname: Won
authors.affiliation: * Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Republic of Korea.
authors.forename: Jun-Hui
authors.initials: JH
authors.lastname: Song
authors.affiliation: * Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Republic of Korea.
authors.forename: Sook-Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: † Personalized Tumor Engineering Research Center, Department of Urology, Chungbuk National University, Cheongju 361-763, Republic of Korea.
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: * Department of Food and Nutrition, Chung-Ang University, Anseong 456-756, Republic of Korea.
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Moon
mesh_terms: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D019306:Artemisia; D006454:Hemoglobins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D008517:Phytotherapy; D014468:Umbelliferones / Q000494:pharmacology* / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000009:adverse effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D006454:Hemoglobins; D014468:Umbelliferones; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D020778:Matrix Metalloproteinase 2; C007628:esculetin
keywords: Angiogenesis; Esculetin; HUVECs; VEGF