title: Targeting of mitogen-activated protein kinases and phosphatidylinositol 3 kinase inhibits hepatocyte growth factor/scatter factor-induced angiogenesis.
abstract: BACKGROUND
  Hepatocyte growth factor/scatter factor (HGF/SF) can sufficiently and independently induce pathophysiological angiogenesis. However, the treatment strategies have mostly been unsuccessful. The present study is the first to evaluate the possible targeting of downstream signals for the inhibition of HGF/SF-induced angiogenesis.
  
  
  RESULTS
  In a multichannel scratch assay with human endothelial cells (ECs), HGF/SF induced a strong and prolonged activation of MAPK and cell proliferation that was inhibited by PD98059 and LY294002/wortmannin, selective inhibitors of MAPK and PI3K signaling modules, respectively. Western blotting demonstrated a temporal relation between the activation of the two pathways. Chemical inhibition of the PI3K and MAPK signals inhibited HGF/SF-induced chemoinvasion of ECs in vitro and blocked the HGF/SF-induced neovascularization into a polymer scaffold in vivo, as quantified by vessel counts and the clearance of radioactive 133Xe.
  
  
  CONCLUSIONS
  These data indicate that MEK and PI3K inhibitors represent a promising approach to the clinical management of pathological conditions characterized by overt HGF/SF-induced angiogenesis.
authors.affiliation: Angiogenesis Laboratory, Department of Pharmacology, University of Cambridge, Cambridge, United Kingdo. shiladit@MIT.edu
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
authors.forename: Lynda A
authors.initials: LA
authors.lastname: Sellers
authors.forename: Rung-Chi
authors.initials: RC
authors.lastname: Li
authors.forename: Ermanno
authors.initials: E
authors.lastname: Gherardi
authors.forename: Ganlin
authors.initials: G
authors.lastname: Zhao
authors.forename: Nicki
authors.initials: N
authors.lastname: Watson
authors.forename: Ram
authors.initials: R
authors.lastname: Sasisekharan
authors.forename: Tai-Ping D
authors.initials: TP
authors.lastname: Fan
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001681:Biological Assay; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D007797:Laminin; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D003094:Collagen; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D005419:Flavonoids; D017228:Hepatocyte Growth Factor; D007797:Laminin; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C059485:matrigel; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one