Differential regulation of diverse physiological responses to VEGF in pulmonary endothelial cells

Patrice M. Becker, Alexander D. Verin, Mary Ann Booth, Feng Liu, Anna Birukova, Joe G.N. Garcia

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

The mechanisms responsible for the divergent physiological responses of endothelial cells to vascular endothelial growth factor (VEGF) are incompletely understood. We hypothesized that VEGF elicits increased endothelial permeability and cell migration via differential activation of intracellular signal transduction pathways. To test this hypothesis, we established a model of VEGF-induced endothelial barrier dysfunction and chemotaxis with bovine pulmonary endothelial cells. We compared the effects of VEGF on transendothelial electrical resistance (TER), actin cytoskeletal remodeling, and chemotaxis of lung endothelial cells and then evaluated the role of the mitogenactivated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK)1/2 in VEGF-mediated endothelial responses. The dose response of pulmonary arterial and lung microvascular endothelial cells to VEGF differed when barrier regulation and chemotaxis were evaluated. Inhibition of tyrosine kinase, phosphoinositol 3-kinase, or p38 MAPK significantly attenuated VEGF-mediated TER, F-actin remodeling, and chemotaxis. VEGF-mediated decreased TER was also significantly attenuated by inhibition of ERK1/2 MAPK but not by inhibition of fetal liver kinase-1 (flk-1) or Src kinase. In contrast, VEGF-mediated endothelial migration was not attenuated by ERK1/2 inhibition but was abolished by inhibition of either flk-1 or Src kinase. These data suggest potential mechanisms by which VEGF may differentially mediate physiological responses in vivo.

Original languageEnglish (US)
Pages (from-to)L1500-L1511
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume281
Issue number6 25-6
DOIs
StatePublished - 2001

Keywords

  • Endothelial barrier dysfunction
  • Endothelial cell chemotaxis
  • Endothelial cell permeability
  • Mitogen-activated protein kinase
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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