title: A Novel Natural Product-Derived Compound, Vestaine A1, Exerts both Pro-Angiogenic and Anti-Permeability Activity via a Different Pathway from VEGF.
abstract: OBJECTIVE
  Vascular endothelial growth factor (VEGF) is a key molecule in the regulation of both angiogenesis and vascular permeability. However, it is known that overproduction of VEGF induces abnormal blood vessel formation and these vessels cause several disease pathologies, such as diabetic retinopathy. The purpose of this study was to find novel vasoactive compounds which have different properties from VEGF.
  
  
  RESULTS
  We screened a natural product library using a co-culture angiogenic assay of endothelial cells and fibroblasts. By focusing on morphological changes of endothelial cells, we isolated the novel compounds vestaine A1 and vestaine B1 from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 63697. Vestaine A1 enhanced tube formation of endothelial cells in Matrigel and suppressed cell death induced by serum deprivation. Vestaine A1 activated both MEK1/2 and PI-3 kinase pathways independently of the VEGF pathway in a dose- and time-dependent fashion. Finally, vestaine A1 potently suppressed VEGF-induced vascular permeability both in vitro and in vivo.
  
  
  CONCLUSIONS
  Vestaine A1 has the potential to exhibit both pro-angiogenic and anti-permeability properties, and would therefore be useful for therapeutic treatment for abnormal vascular permeability-related diseases.
authors: Frontier Research Laboratories IV, R&amp;D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors: Yoko
authors: Y
authors: Ishimoto
authors: Yuki
authors: Y
authors: Hirota-Takahata
authors: Emi
authors: E
authors: Kurosawa
authors: Jun
authors: J
authors: Chiba
authors: Yuko
authors: Y
authors: Iwadate
authors: Yoshiko
authors: Y
authors: Onozawa
authors: Toru
authors: T
authors: Hasegawa
authors: Akihiro
authors: A
authors: Tamura
authors: Masahiro
authors: M
authors: Tanaka
authors: Hideki
authors: H
authors: Kobayashi
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D043925:Angiogenesis Inducing Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000737:chemistry; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D011509:Proteoglycans / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013302:Streptomyces / Q000737:chemistry* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D043925:Angiogenesis Inducing Agents; D001688:Biological Products; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D000644:Quaternary Ammonium Compounds; D054852:Small Molecule Libraries; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000613967:vestaine A1; C059485:matrigel; D003094:Collagen; C482128:MAP2K2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D000111:Acetylcysteine