Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

Anna A. Birukova, Tatiana Zagranichnaya, Panfeng Fu, Elena Alekseeva, Weiguo Chen, Jeffrey R. Jacobson, Konstantin G. Birukov

Research output: Contribution to journalArticlepeer-review

240 Scopus citations

Abstract

Prostaglandin E2 (PGE2) and prostacyclin are lipid mediators produced by cyclooxygenase and implicated in the regulation of vascular function, wound repair, inflammatory processes, and acute lung injury. Although protective effects of these prostaglandins (PGs) are associated with stimulation of intracellular cAMP production, the crosstalk between cAMP-activated signal pathways in the regulation of endothelial cell (EC) permeability is not well understood. We studied involvement of cAMP-dependent kinase (PKA), cAMP-Epac-Rap1 pathway, and small GTPase Rac in the PGs-induced EC barrier protective effects and cytoskeletal remodeling. PGE2 and PGI2 synthetic analog beraprost increased transendothelial electrical resistance and decreased dextran permeability, enhanced peripheral F-actin rim and increased intercellular adherens junction areas reflecting EC barrier-protective response. Furthermore, beraprost dramatically attenuated thrombin-induced Rho activation, MLC phosphorylation and EC barrier dysfunction. In vivo, beraprost attenuated lung barrier dysfunction induced by high tidal volume mechanical ventilation. Both PGs caused cAMP-mediated activation of PKA-, Epac/Rap1- and Tiam1/Vav2-dependent pathways of Rac1 activation and EC barrier regulation. Knockdown of Epac, Rap1, Rac-specific exchange factors Tiam1 and Vav2 using siRNA approach, or inhibition of PKA activity decreased Rac1 activation and PG-induced EC barrier enhancement. Thus, our results show that barrier-protective effects of PGE2 and prostacyclin on pulmonary EC are mediated by PKA and Epac/Rap pathways, which converge on Rac activation and lead to enhancement of peripheral actin cytoskeleton and adherens junctions. These mechanisms may mediate protective effects of PGs against agonist-induced lung vascular barrier dysfunction in vitro and against mechanical stress-induced lung injury in vivo.

Original languageEnglish
Pages (from-to)2504-2520
Number of pages17
JournalExperimental Cell Research
Volume313
Issue number11
DOIs
StatePublished - Jul 1 2007

Bibliographical note

Funding Information:
This work was supported by grants from the National Heart, Lung, and Blood Institutes (HL076259 and HL075349) for KGB and the AHA Scientist Development Grant for AAB. The authors wish to thank Nurgul Moldobaeva for superb laboratory assistance.

Keywords

  • Cytoskeleton
  • GEFs
  • Lung endothelium
  • PKA
  • Permeability
  • Small GTPases

ASJC Scopus subject areas

  • Cell Biology

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