Time course of thrombin-induced increase in endothelial permeability: Relationship to Ca(i)/2+ and inositol polyphosphates

H. Lum, J. L. Aschner, P. G. Phillips, P. W. Fletcher, A. B. Malik

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

The temporal relationship between the α-thrombin-induced increase in transendothelial permeability and the α-thrombin-mediated changes in several key transmembrane signaling events was examined in confluent monolayers of bovine pulmonary artery endothelial cells (BPAEC). The time courses of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] generation, changes in cytosolic [Ca2+] ([Ca2+](i)), and reorganization of cytoskeletal F-actin were determined to assess the relationship between these events and the onset of the α-thrombin-induced increase in endothelial permeability. α-Thrombin (10-7 M) increased the transendothelial 125I-albumin clearance rate half-maximally by ~1 min and maximally by ~2 min (160% over control level). The increase in permeability occurred concomitantly with reorganization of F- actin cytoskeleton (i.e., loss of peripheral band and increased stress fiber density) and increased actin polymerization. Stimulation of fura-2-loaded BPAEC with 10-7 M α-thrombin produced a typical biphasic rise in [Ca2+](i). The initial rapid increase in [Ca2+](i) peaked by ~16 s after thrombin challenge and the [Ca2+](i) response showed a slow decrease to half-maximal within 50 s. The α-thrombin-induced increase in permeability as well as the increase in [Ca2+](i) were consistently preceded by increased Ins(1,4,5)P3 generation detectable within 10 s after thrombin challenge. These results indicate that α-thrombin triggers a cascade of events {i.e., Ins(1,4,5)P3 generation and the ensuing rise in [Ca2+](i)}, which may comprise the second messengers that mediate F-actin reorganization and the increase in endothelial permeability.

Original languageEnglish (US)
Pages (from-to)L219-L225
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume263
Issue number2 7-2
StatePublished - Jan 1 1992

Keywords

  • actin cytoskeleton
  • cytosolic calcium
  • endothelial permeability
  • inositol 1,3,4,5-tetrakisphosphate
  • inositol 1,3,4-trisphosphate
  • inositol 1,4,5- trisphosphate
  • inositol bisphosphates
  • peripheral actin band
  • stress fibers
  • α- thrombin

ASJC Scopus subject areas

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

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