PMID- 12524227
OWN - NLM
STAT- MEDLINE
DCOM- 20030127
LR  - 20211203
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Linking)
VI  - 23
IP  - 1
DP  - 2003 Jan 1
TI  - Hepatocyte growth factor/scatter factor can induce angiogenesis independently of 
      vascular endothelial growth factor.
PG  - 69-75
AB  - OBJECTIVE: Hepatocyte growth factor/scatter factor (HGF/SF) promotes vascular 
      endothelial growth factor (VEGF) expression and induces angiogenesis in multiple 
      pathological conditions. The present study was designed to delineate the HGF/SF 
      and VEGF signaling cascades during angiogenesis by using PTK787, a selective VEGF 
      receptor antagonist. METHODS AND RESULTS: PTK787 produced a 
      concentration-dependent (10(-8) to 10(-6) mol/L) inhibition of VEGF-induced 
      angiogenesis, without altering the basal or HGF/SF-induced response in vitro. In 
      contrast, the nonspecific kinase inhibitor genistein blocked the HGF/SF-induced 
      effect. Both VEGF and HGF/SF induced a rapid phosphorylation of extracellular 
      receptor kinases-1 and -2 (ERKs) and Akt. PTK787 inhibited the VEGF-induced 
      activation of Akt and ERKs, without affecting the HGF/SF-induced phosphorylation. 
      Treatment with VEGF and HGF/SF increased total neovascularization in a murine 
      scaffold granuloma model, but no additive or synergistic interactions were 
      observed. PTK787 (50 mg/kg) blocked the VEGF-induced response without altering 
      the basal or HGF/SF-induced neovascularization. CONCLUSIONS: We demonstrate that 
      HGF/SF can induce angiogenesis independently of VEGF, possibly through the direct 
      activation of the Akt and ERKs. These results demonstrate the necessity of a 
      multitargeted approach for the rational design of newer therapies to inhibit 
      pathophysiological angiogenesis.
FAU - Sengupta, Shiladitya
AU  - Sengupta S
AD  - Angiogenesis Laboratory, Department of Pharmacology, University of Cambridge, 
      Cambridge, England. shiladit@MIT.edu
FAU - Gherardi, Ermanno
AU  - Gherardi E
FAU - Sellers, Lynda A
AU  - Sellers LA
FAU - Wood, Jeanette M
AU  - Wood JM
FAU - Sasisekharan, Ram
AU  - Sasisekharan R
FAU - Fan, Tai-Ping D
AU  - Fan TP
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Lymphokines)
RN  - 0 (Phthalazines)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Pyridines)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 5DX9U76296 (vatalanib)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
RN  - EC 2.7.11.1 (AKT1 protein, human)
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)
SB  - IM
MH  - Animals
MH  - Cell Division/drug effects/physiology
MH  - Cells, Cultured
MH  - Endothelial Growth Factors/antagonists & 
      inhibitors/biosynthesis/genetics/*physiology
MH  - Endothelium, Vascular/drug effects/enzymology/injuries/pathology
MH  - Enzyme Activation/drug effects/physiology
MH  - Hepatocyte Growth Factor/metabolism/*physiology
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/biosynthesis/genetics/*physiology
MH  - Lymphokines/antagonists & inhibitors/biosynthesis/genetics/*physiology
MH  - MAP Kinase Signaling System/drug effects/physiology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors/physiology
MH  - Neovascularization, Pathologic/*physiopathology
MH  - Phosphorylation/drug effects
MH  - Phthalazines/pharmacology
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors/physiology
MH  - *Proto-Oncogene Proteins
MH  - Proto-Oncogene Proteins c-akt
MH  - *Pyridines
MH  - Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors/physiology
MH  - Recombinant Proteins/antagonists & inhibitors/biosynthesis/genetics
MH  - Transfection
MH  - Tumor Cells, Cultured
MH  - Umbilical Veins/drug effects/enzymology/pathology
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 2003/01/14 04:00
MHDA- 2003/01/28 04:00
CRDT- 2003/01/14 04:00
PHST- 2003/01/14 04:00 [pubmed]
PHST- 2003/01/28 04:00 [medline]
PHST- 2003/01/14 04:00 [entrez]
AID - 10.1161/01.atv.0000048701.86621.d0 [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2003 Jan 1;23(1):69-75. doi: 
      10.1161/01.atv.0000048701.86621.d0.