Caveolae are an essential component of the pathway for endothelial cell signaling associated with abrupt reduction of shear stress

Tatyana Milovanova, Shampa Chatterjee, Brian J. Hawkins, Nan Kang Hong, Elena M. Sorokina, Kris DeBolt, Jonni S. Moore, Muniswamy Madesh, Aron B. Fisher

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

Abrupt cessation of flow representing the acute loss of shear stress (simulated ischemia) to flow-adapted pulmonary microvascular endothelial cells (PMVEC) leads to reactive oxygen species (ROS) generation that signals for EC proliferation. We evaluated the role of caveolin-1 on this cellular response with mouse PMVEC that were preconditioned for 72 h to laminar flow at 5 dyn/cm2 followed by stop of flow ("ischemia"). Preconditioning resulted in a 2.7-fold increase in cellular expression of KATP (KIR 6.2) channels but no change in expression level of caveolin-1, gp91phox, or MAP kinases. The initial response to ischemia in wild type cells was cell membrane depolarization that was abolished by gene targeting of KIR 6.2. The subsequent response was increased ROS production associated with activation of NADPH oxidase (NOX2) and then phosphorylation of MAP kinases (Erk, JNK). After 24 h of ischemia in wild type cells, the cell proliferation index increased 2.5 fold and the % of cells in S + G2/M phases increased 6-fold. This signaling cascade (cell membrane depolarization, ROS production, MAP kinase activation and cell proliferation) was abrogated in caveolin-1 null PMVEC or by treatment of wild type cells with filipin. These studies indicate that caveolin-1 functions as a shear sensor in flow-adapted EC resulting in ROS-mediated cell signaling and endothelial cell proliferation following the abrupt reduction in flow.

Original languageEnglish (US)
Pages (from-to)1866-1875
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1783
Issue number10
DOIs
StatePublished - Oct 2008

Keywords

  • Cell proliferation
  • K channel
  • Mechanotransduction
  • NADPH oxidase
  • Pulmonary microvascular endothelium
  • Reactive oxygen species
  • Shear stress

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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