Article Text

  1. T. Mirzapoiazova,
  2. I. Kolosova,
  3. P. Usatyuk,
  4. V. Natarajan,
  5. A. D. Verin
  1. Johns Hopkins University School of Medicine, Baltimore


Increased endothelial permeability is involved in the pathogenesis of many cardiovascular and pulmonary diseases. Vascular endothelial growth factor (VEGF) is considered to be a major permeability increasing cytokine. On the other hand, VEGF is known to have beneficial effect on endothelial cells (EC), increasing their survival. In most cases barrier-disruptive properties of VEGF were observed at rather high concentrations, while lower concentrations induce cell migration and proliferation. We found that 10 ng/mL VEGF significantly improved barrier properties of cultured human pulmonary artery EC (HPAEC), as indicated by transendothelial resistance measurement (20 ± 2.6% increase, p<0.01), while 100 ng/mL VEGF had barrier-disruptive effect (40 ± 3.2% decrease, p<0.01). Consistent with these data EC-treatment with 10 ng/mL VEGF enhanced VE-cadherin staining at the cell periphery, suggesting stabilization of cell-cell contacts. Level of myosin light chain phosphorylation (an index of EC contraction and barrier disruption) was dramatically increased after treatment with 100 ng/mL, but not with 10 ng/mL VEGF. In contrast, 10 ng/mL, but not 100 ng/mL, VEGF caused significant increase in intracellular cAMP (known barrier-protective stimulus) compared with non-stimulated cells (610 ± 86 and 1096 ± 157 fmol/mg protein respectively, p<0.024). Stimulation with 10 ng/mL, but not with 100 ng/mL, VEGF caused translocation of delta, but not alfa and beta of protein kinase C (PKC) isoforms to the plasma membrane indicating their activation. PKC inhibitor Ro 31-8220 significantly attenuated barrier-enhancing effect of 10 ng/mL VEGF with minimal effect on permeability induced by 100 ng/mL VEGF. Collectively, these data suggest that low VEGF concentration may protect endothelial monolayer integrity via increase in cAMP production and activation of specific PKC isoforms.

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