Magnitude-dependent regulation of pulmonary endothelial cell barrier function by cyclic stretch

Konstantin G. Birukov, Jeffrey R. Jacobson, Alejandro A. Flores, Shui Q. Ye, Anna A. Birukova, Alexander D. Verin, Joe G.N. Garcia

Research output: Contribution to journalArticle

188 Scopus citations

Abstract

Ventilator-induced lung injury syndromes are characterized by profound increases in vascular leakiness and activation of inflammatory processes. To explore whether excessive cyclic stretch (CS) directly causes vascular barrier disruption or enhances endothelial cell sensitivity to edemagenic agents, human pulmonary artery endothelial cells (HPAEC) were exposed to physiologically (5% elongation) or pathologically (18% elongation) relevant levels of strain. CS produced rapid (10 min) increases in myosin light chain (MLC) phosphorylation, activation of p38 and extracellular signal-related kinase 1/2 MAP kinases, and actomyosin remodeling. Acute (15 min) and chronic (48 h) CS markedly enhanced thrombin-induced MLC phosphorylation (2.1-fold and 3.2-fold for 15-min CS at 5 and 18% elongation and 2.1-fold and 3.1-fold for 48-h CS at 5 and 18% elongation, respectively). HPAEC preconditioned at 18% CS, but not at 5% CS, exhibited significantly enhanced thrombin-induced reduction in transendothelial electrical resistance but did not affect barrier protective effect of sphingosine-1-phosphate (0.5 μM). Finally, expression profiling analysis revealed a number of genes, including small GTPase rho, apoptosis mediator ZIP kinase, and proteinase activated receptor-2, to be regulated by CS in an amplitude-dependent manner. Thus our study demonstrates a critical role for the magnitude of CS in regulation of agonist-mediated pulmonary endothelial cell permeability and strongly suggests phenotypic regulation of HPAEC barrier properties by CS.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume285
Issue number4 29-4
Publication statusPublished - Oct 1 2003
Externally publishedYes

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Keywords

  • Actin
  • Cytoskeleton
  • Mechanical strain
  • Myosin
  • Permeability
  • Phosphorylation
  • Thrombin

ASJC Scopus subject areas

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

Cite this

Birukov, K. G., Jacobson, J. R., Flores, A. A., Ye, S. Q., Birukova, A. A., Verin, A. D., & Garcia, J. G. N. (2003). Magnitude-dependent regulation of pulmonary endothelial cell barrier function by cyclic stretch. American Journal of Physiology - Lung Cellular and Molecular Physiology, 285(4 29-4).