PMID- 20089873
OWN - NLM
STAT- MEDLINE
DCOM- 20100611
LR  - 20211020
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 51
IP  - 6
DP  - 2010 Jun
TI  - Antipermeability function of PEDF involves blockade of the MAP 
      kinase/GSK/beta-catenin signaling pathway and uPAR expression.
PG  - 3273-80
LID - 10.1167/iovs.08-2878 [doi]
AB  - PURPOSE: Pigment epithelium-derived factor (PEDF) is a potent inhibitor of 
      vascular endothelial growth factor (VEGF)-induced endothelial permeability. The 
      goal of this study was to understand the mechanism by which PEDF blocks 
      VEGF-induced increases in vascular permeability. METHODS: The paracellular 
      permeability of bovine retinal endothelial (BRE) cells was measured by assaying 
      transendothelial cell electrical resistance and tracer flux. Western blot 
      analysis was used to show phosphorylation of VEGFR2, MAP kinases, and glycogen 
      synthase kinase 3 (GSK3)-beta. Confocal imaging and Western blot analysis were 
      used to determine subcellular distribution of beta-catenin. Real-time RT-PCR and 
      Western blot analysis were used to quantify urokinase plasminogen activator 
      receptor (uPAR) expression. RESULTS: PEDF blocked VEGF-induced phosphorylation of 
      extracellular signal-regulated kinase (ERK), p38 MAP kinase, the p38 substrate 
      MAP kinase-activated protein kinase-2 (MAPKAPK-2), and GSK3-beta, but it had no 
      effect on the phosphorylation of VEGFR2. In addition, the VEGF-induced 
      transcriptional activation of beta-catenin and uPAR expression were blocked by 
      PEDF and by inhibitors of p38 and MEK. Finally, the VEGF-induced increase in 
      permeability was blocked by both PEDF and the same kinase inhibitors. 
      CONCLUSIONS: The data suggest that p38 MAP kinase and ERK act upstream of 
      GSK/beta-catenin in VEGF-induced activation of the uPA/uPAR system and that 
      PEDF-mediated inhibition of the VEGF-induced increase in vascular permeability 
      involves blockade of this pathway. These findings are important for developing 
      precise and potent therapies for treatment of diseases characterized by vascular 
      barrier dysfunction.
FAU - Yang, Jinling
AU  - Yang J
AD  - VA Medical Center, Augusta, Georgia, USA.
FAU - Duh, Elia J
AU  - Duh EJ
FAU - Caldwell, Ruth B
AU  - Caldwell RB
FAU - Behzadian, M Ali
AU  - Behzadian MA
LA  - eng
GR  - R01 EY004618/EY/NEI NIH HHS/United States
GR  - R01 EY011766/EY/NEI NIH HHS/United States
GR  - EY011766/EY/NEI NIH HHS/United States
GR  - EY004618/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100120
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (Dextrans)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Eye Proteins)
RN  - 0 (Nerve Growth Factors)
RN  - 0 (Receptors, Urokinase Plasminogen Activator)
RN  - 0 (Serpins)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (beta Catenin)
RN  - 0 (fluorescein isothiocyanate dextran)
RN  - 0 (pigment epithelium-derived factor)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - I223NX31W9 (Fluorescein-5-isothiocyanate)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Capillary Permeability/*drug effects
MH  - Cattle
MH  - Dextrans/metabolism
MH  - Electric Impedance
MH  - Endothelium, Vascular/drug effects/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Eye Proteins/*pharmacology
MH  - Fluorescein-5-isothiocyanate/analogs & derivatives/metabolism
MH  - Glycogen Synthase Kinase 3/*antagonists & inhibitors/metabolism
MH  - Glycogen Synthase Kinase 3 beta
MH  - Immunohistochemistry
MH  - Microscopy, Confocal
MH  - Mitogen-Activated Protein Kinases/*antagonists & inhibitors/metabolism
MH  - Nerve Growth Factors/*pharmacology
MH  - Phosphorylation
MH  - Receptors, Urokinase Plasminogen Activator/*metabolism
MH  - Retinal Vessels/cytology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Serpins/*pharmacology
MH  - Signal Transduction/*drug effects
MH  - Vascular Endothelial Growth Factor A/pharmacology
MH  - beta Catenin/*antagonists & inhibitors/metabolism
PMC - PMC2891479
EDAT- 2010/01/22 06:00
MHDA- 2010/06/12 06:00
PMCR- 2010/12/01
CRDT- 2010/01/22 06:00
PHST- 2010/01/22 06:00 [entrez]
PHST- 2010/01/22 06:00 [pubmed]
PHST- 2010/06/12 06:00 [medline]
PHST- 2010/12/01 00:00 [pmc-release]
AID - iovs.08-2878 [pii]
AID - 08-2878 [pii]
AID - 10.1167/iovs.08-2878 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2010 Jun;51(6):3273-80. doi: 10.1167/iovs.08-2878. 
      Epub 2010 Jan 20.