PMID- 10211995
OWN - NLM
STAT- MEDLINE
DCOM- 19990513
LR  - 20091119
IS  - 0023-6837 (Print)
IS  - 0023-6837 (Linking)
VI  - 79
IP  - 4
DP  - 1999 Apr
TI  - Hepatocyte growth factor increases expression of vascular endothelial growth 
      factor and plasminogen activator inhibitor-1 in human keratinocytes and the 
      vascular endothelial growth factor receptor flk-1 in human endothelial cells.
PG  - 427-38
AB  - The pleiotropic growth factor hepatocyte growth factor/scatter factor (HGF/SF) 
      has been implicated by clinical and experimental studies in repair mechanisms in 
      different organs and tissues. However, no data on the impact of HGF/SF in wound 
      healing in the skin are yet available. Proliferating and migrating keratinocytes 
      play a major role in repair processes in the skin by closing the wound. Recent 
      evidence gathered from studies that used gene-deficient mice has implicated the 
      plasminogen activator (PA)/plasmin system in wound healing, which depends on 
      controlled matrix degradation and deposition during cell migration and 
      proliferation. Furthermore, keratinocytes are an important source of vascular 
      endothelial growth factor (VEGF), which is a potent inducer of angiogenesis. In 
      this study, we show that in human keratinocytes HGF/SF but not the related 
      cytokine macrophage stimulating protein (MSP) significantly increases expression 
      of VEGF and plasminogen activator inhibitor-1 (PAI-1) on the level of protein and 
      mRNA. Furthermore, we demonstrate that HGF/SF increases the expression of the 
      VEGF receptor flk-1 in human endothelial cells and that, in an angiogenesis 
      co-culture assay of endothelial cells and keratinocytes, HGF/SF increases 
      endothelial cell tube formation significantly. Therefore, we propose a role for 
      HGF/SF in wound repair in the skin: HGF/SF--produced by activated 
      fibroblasts--increases in keratinocytes the expression of PAI-1, which leads to 
      increased matrix stability during the repair process and which could also limit 
      activation of HGF/SF by proteases such as urokinase-type PA (u-PA) or tissue-type 
      PA (t-PA). Furthermore HGF/SF also increases the expression of VEGF in these 
      cells, thereby initiating angiogenesis in a paracrine manner. This effect would 
      be enhanced by an increased responsiveness of endothelial cells toward VEGF, 
      resulting from the HGF/SF-induced up-regulation of flk-1 on these cells.
FAU - Wojta, J
AU  - Wojta J
AD  - Department of Vascular Biology and Thrombosis Research, University of Vienna, 
      Austria.
FAU - Kaun, C
AU  - Kaun C
FAU - Breuss, J M
AU  - Breuss JM
FAU - Koshelnick, Y
AU  - Koshelnick Y
FAU - Beckmann, R
AU  - Beckmann R
FAU - Hattey, E
AU  - Hattey E
FAU - Mildner, M
AU  - Mildner M
FAU - Weninger, W
AU  - Weninger W
FAU - Nakamura, T
AU  - Nakamura T
FAU - Tschachler, E
AU  - Tschachler E
FAU - Binder, B R
AU  - Binder BR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Lab Invest
JT  - Laboratory investigation; a journal of technical methods and pathology
JID - 0376617
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (Growth Substances)
RN  - 0 (Lymphokines)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Growth Factor)
RN  - 0 (Receptors, Mitogen)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Vascular Endothelial Growth Factors)
RN  - 0 (macrophage stimulating protein)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor)
RN  - EC 3.4.21.68 (Tissue Plasminogen Activator)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
SB  - IM
MH  - Animals
MH  - Cell Division
MH  - Cell Line, Transformed
MH  - Cells, Cultured
MH  - Coculture Techniques
MH  - Culture Media, Conditioned
MH  - Endothelial Growth Factors/*genetics
MH  - Endothelium, Vascular/cytology/drug effects/*metabolism
MH  - Gene Expression Regulation/*drug effects
MH  - Growth Substances/pharmacology
MH  - Hepatocyte Growth Factor/*pharmacology/physiology
MH  - Humans
MH  - Keratinocytes/drug effects/*metabolism
MH  - Lymphokines/*genetics
MH  - Mice
MH  - Neovascularization, Physiologic/drug effects/*physiology
MH  - Plasminogen Activator Inhibitor 1/*genetics
MH  - *Proto-Oncogene Proteins
MH  - Receptor Protein-Tyrosine Kinases/*genetics
MH  - Receptors, Growth Factor/*genetics
MH  - Receptors, Mitogen/genetics
MH  - Receptors, Vascular Endothelial Growth Factor
MH  - Recombinant Proteins/pharmacology
MH  - Tissue Plasminogen Activator/genetics
MH  - Umbilical Veins
MH  - Urokinase-Type Plasminogen Activator/genetics
MH  - Vascular Endothelial Growth Factor A
MH  - Vascular Endothelial Growth Factors
EDAT- 1999/04/22 00:00
MHDA- 1999/04/22 00:01
CRDT- 1999/04/22 00:00
PHST- 1999/04/22 00:00 [pubmed]
PHST- 1999/04/22 00:01 [medline]
PHST- 1999/04/22 00:00 [entrez]
PST - ppublish
SO  - Lab Invest. 1999 Apr;79(4):427-38.