PMID- 12782568
OWN - NLM
STAT- MEDLINE
DCOM- 20030701
LR  - 20211203
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 107
IP  - 23
DP  - 2003 Jun 17
TI  - Targeting of mitogen-activated protein kinases and phosphatidylinositol 3 kinase 
      inhibits hepatocyte growth factor/scatter factor-induced angiogenesis.
PG  - 2955-61
AB  - 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. METHODS AND 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.
FAU - Sengupta, Shiladitya
AU  - Sengupta S
AD  - Angiogenesis Laboratory, Department of Pharmacology, University of Cambridge, 
      Cambridge, United Kingdo. shiladit@MIT.edu
FAU - Sellers, Lynda A
AU  - Sellers LA
FAU - Li, Rung-Chi
AU  - Li RC
FAU - Gherardi, Ermanno
AU  - Gherardi E
FAU - Zhao, Ganlin
AU  - Zhao G
FAU - Watson, Nicki
AU  - Watson N
FAU - Sasisekharan, Ram
AU  - Sasisekharan R
FAU - Fan, Tai-Ping D
AU  - Fan TP
LA  - eng
PT  - Journal Article
DEP - 20030602
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Androstadienes)
RN  - 0 (Chromones)
RN  - 0 (Drug Combinations)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Flavonoids)
RN  - 0 (Laminin)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Proteoglycans)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 119978-18-6 (matrigel)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - 9007-34-5 (Collagen)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Animals
MH  - Biological Assay
MH  - Cell Division/drug effects
MH  - Cells, Cultured
MH  - Chromones/pharmacology
MH  - Collagen
MH  - Drug Combinations
MH  - Endothelium, Vascular/cytology/drug effects
MH  - Enzyme Inhibitors/*pharmacology
MH  - Flavonoids/pharmacology
MH  - Hepatocyte Growth Factor/*antagonists & inhibitors/pharmacology
MH  - Humans
MH  - Laminin
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mitogen-Activated Protein Kinases/*antagonists & inhibitors/metabolism
MH  - Morpholines/pharmacology
MH  - Neovascularization, Physiologic/*drug effects
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - *Protein Serine-Threonine Kinases
MH  - Proteoglycans
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Signal Transduction/drug effects
MH  - Wortmannin
EDAT- 2003/06/05 05:00
MHDA- 2003/07/02 05:00
CRDT- 2003/06/05 05:00
PHST- 2003/06/05 05:00 [pubmed]
PHST- 2003/07/02 05:00 [medline]
PHST- 2003/06/05 05:00 [entrez]
AID - 01.CIR.0000077501.19266.E5 [pii]
AID - 10.1161/01.CIR.0000077501.19266.E5 [doi]
PST - ppublish
SO  - Circulation. 2003 Jun 17;107(23):2955-61. doi: 
      10.1161/01.CIR.0000077501.19266.E5. Epub 2003 Jun 2.