VEGF increases endothelial permeability by separate signaling pathways involving ERK-1/2 and nitric oxide

Jerome W. Breslin, Peter J. Pappas, Joaquim J. Cerveira, Robert W. Hobson, Walter N. Duran

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135 Scopus citations


We tested the hypothesis that VEGF regulates endothelial hyperpermeability to macromolecules by activating the ERK-1/2 MAPK pathway. We also tested whether PKC and nitric oxide (NO) mediate VEGF-induced increases in permeability via the ERK-1/2 pathway. FITC-Dextran 70 flux across human umbilical vein endothelial cell monolayers served as an index of permeability, whereas Western blots assessed the phosphorylation of ERK-1/2. VEGF-induced hyperpermeability was inhibited by antisense DNA oligonucleotides directed against ERK-1/2 and by blockade of MEK and Raf-1 activities (20 μM PD-98059 and 5 μM GW-5074). These blocking agents also reduced ERK-1/2 phosphorylation. The PKC inhibitor bisindolylmaleimide I (10 μM) blocked both VEGF-induced ERK-1/2 activation and hyperpermeability. The NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (200 μM) and the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidiazoline-1-oxyl-3-oxide (100 μM) abolished VEGFinduced hyperpermeability but did not block ERK-1/2 phosphorylation. These observations demonstrate VEGF-induced hyperpermeability involves activation of PKC and NOS as well as Raf-1, MEK, and ERK-1/2. Furthermore, our data suggest that ERK-1/2 and NOS are elements of different signaling pathways in VEGF-induced hyperpermeability.

Original languageEnglish (US)
Pages (from-to)H92-H100
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number1 53-1
StatePublished - Jan 1 2003

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


  • Endothelial cells
  • Microvascular permeability
  • Mitogen-activated protein kinases
  • Protein kinase C
  • Vascular endothelial growth factor

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