ET-1- and NO-mediated signal transduction pathway in human brain capillary endothelial cells

Y. Chen, R. M. McCarron, S. Golech, J. Bembry, B. Ford, F. A. Lenz, N. Azzam, M. Spatz

Research output: Contribution to journalReview article

Abstract

Previous studies have demonstrated that functional interaction between endothelin (ET)-1 and nitric oxide (NO) involves changes in Ca2+ mobilization and cytoskeleton in human brain microvascular endothelial cells. The focus of this investigation was to examine the possible existence of analogous interplay between these vasoactive substances and elucidate their signal transduction pathways in human brain capillary endothelial cells. The results indicate that ET-1-stimulated Ca2+ mobilization in these cells is dose-dependently inhibited by NOR-1 (an NO donor). This inhibition was prevented by ODQ (an inhibitor of guanylyl cyclase) or Rp-8-CPT-cGMPS (an inhibitor of protein kinase G). Treatment of endothelial cells with 8-bromo-cGMP reduced ET-1-induced Ca2+ mobilization in a manner similar to that observed with NOR-1 treatment. In addition, NOR-1 or cGMP reduced Ca2+ mobilization induced by mastoparan (an activator of G protein), inositol 1,4,5-trisphosphate, or thapsigargin (an inhibitor of Ca2+ -ATPase). Interestingly, alterations in endothelial cytoskeleton (actin and vimentin) were associated with these effects. The data indicate for the first time that the cGMP-dependent protein kinase colocalizes with actin. These changes were accompanied by altered levels of phosphorylated vasodilator-stimulated phosphoprotein, which were elevated in endothelial cells incubated with NOR-1 and significantly reduced by ODQ or Rp-8-CPT-cGMPS. The findings indicate a potential mechanism by which the functional interrelationship between ET-1 and NO plays a role in regulating capillary tone, microcirculation, and blood-brain barrier function.

Original languageEnglish (US)
Pages (from-to)C243-C249
JournalAmerican Journal of Physiology - Cell Physiology
Volume284
Issue number2 53-2
StatePublished - Feb 1 2003

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Keywords

  • Calcium mobilization
  • Capillary endothelium
  • Cytoskeleton
  • Endothelin-1
  • Nitric oxide

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this

Chen, Y., McCarron, R. M., Golech, S., Bembry, J., Ford, B., Lenz, F. A., Azzam, N., & Spatz, M. (2003). ET-1- and NO-mediated signal transduction pathway in human brain capillary endothelial cells. American Journal of Physiology - Cell Physiology, 284(2 53-2), C243-C249.