Microtubule disassembly increases endothelial cell barrier dysfunction: Role of MLC phosphorylation

Alexander D. Verin, Anna Birukova, Peiyi Wang, Liu Feng, Patrice Becker, Konstantin Birukov, Joe G.N. Garcia

Research output: Contribution to journalArticlepeer-review

139 Scopus citations

Abstract

Endothelial cell (EC) barrier regulation is critically dependent on cytoskeletal components (microfilaments and microtubules). Because several edemagenic agents induce actomyosin-driven EC contraction tightly linked to myosin light chain (MLC) phosphorylation and microfilament reorganization, we examined the role of microtubule components in bovine EC barrier regulation. Nocodazole or vinblastine, inhibitors of microtubule polymerization, significantly decreased transendothelial electrical resistance in a dose-dependent manner, whereas pretreatment with the microtubule stabilizer paclitaxel significantly attenuated this effect. Decreases in transendothelial electrical resistance induced by microtubule disruption correlated with increases in lung permeability in isolated ferret lung preparations as well as with increases in EC stress fiber content and MLC phosphorylation. The increases in MLC phosphorylation were attributed to decreases in myosin-specific phosphatase activity without significant increases in MLC kinase activity and were attenuated by paclitaxel or by several strategies (C3 exotoxin, toxin B, Rho kinase inhibition) to inhibit Rho GTPase. Together, these results suggest that microtubule disruption initiates specific signaling pathways that cross talk with microfilament networks, resulting in Rho-mediated EC contractility and barrier dysfunction.

Original languageEnglish (US)
Pages (from-to)L565-L574
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume281
Issue number3 25-3
DOIs
StatePublished - 2001

Keywords

  • Actin rearrangement
  • Nonmuscle contraction
  • Transendothelial electrical resistance

ASJC Scopus subject areas

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

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