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

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

Research output: Contribution to journalArticle

83 Citations (Scopus)

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)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume281
Issue number6 25-6
StatePublished - Dec 31 2001
Externally publishedYes

Fingerprint

Vascular Endothelial Growth Factor A
Endothelial Cells
Lung
Chemotaxis
Electric Impedance
Vascular Endothelial Growth Factor Receptor-2
src-Family Kinases
p38 Mitogen-Activated Protein Kinases
Actins
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Protein-Tyrosine Kinases
Protein Kinases
Cell Movement
Permeability
Signal Transduction
Phosphotransferases
Inhibition (Psychology)

Keywords

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

ASJC Scopus subject areas

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

Cite this

Differential regulation of diverse physiological responses to VEGF in pulmonary endothelial cells. / Becker, Patrice M.; Verin, Alexander Dmitriyevich; Booth, Mary Ann; Liu, Feng; Birukova, Anna; Garcia, Joe G N.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 281, No. 6 25-6, 31.12.2001.

Research output: Contribution to journalArticle

@article{2458f2654d8146d99ee963620d1e093f,
title = "Differential regulation of diverse physiological responses to VEGF in pulmonary endothelial cells",
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.",
keywords = "Endothelial barrier dysfunction, Endothelial cell chemotaxis, Endothelial cell permeability, Mitogen-activated protein kinase, Vascular endothelial growth factor",
author = "Becker, {Patrice M.} and Verin, {Alexander Dmitriyevich} and Booth, {Mary Ann} and Feng Liu and Anna Birukova and Garcia, {Joe G N}",
year = "2001",
month = "12",
day = "31",
language = "English (US)",
volume = "281",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "6 25-6",

}

TY - JOUR

T1 - Differential regulation of diverse physiological responses to VEGF in pulmonary endothelial cells

AU - Becker, Patrice M.

AU - Verin, Alexander Dmitriyevich

AU - Booth, Mary Ann

AU - Liu, Feng

AU - Birukova, Anna

AU - Garcia, Joe G N

PY - 2001/12/31

Y1 - 2001/12/31

N2 - 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.

AB - 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.

KW - Endothelial barrier dysfunction

KW - Endothelial cell chemotaxis

KW - Endothelial cell permeability

KW - Mitogen-activated protein kinase

KW - Vascular endothelial growth factor

UR - http://www.scopus.com/inward/record.url?scp=0035217482&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035217482&partnerID=8YFLogxK

M3 - Article

C2 - 11704547

AN - SCOPUS:0035217482

VL - 281

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 6 25-6

ER -