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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