Inhibition of endothelial cell migration, intercellular communication, and vascular tube formation by thromboxane A2

Anthony W. Ashton, Ryoji Yokota, Gareth John, Shumin Zhao, Sylvia O. Suadicani, David C. Spray, J. Anthony Ware

Research output: Contribution to journalArticle

135 Scopus citations

Abstract

The eicosanoid thromboxane A2 (TXA2) is released by activated platelets, monocytes, and the vessel wall and interacts with high affinity receptors expressed in several tissues including endothelium. Whether TXA2 might alter endothelial migration and tube formation, two determinants of angiogenesis, is unknown. Thus, we investigated the effect of the TXA2 mimetic [1S-(1α,2β(5Z),3α(1E,3R),4α]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)- 1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5'-heptenoic acid (IBOP) on human endothelial cell (HEC) migration and angiogenesis in vitro. IBOP stimulation inhibited HEC migration by 50% and in vitro capillary formation by 75%. These effects of IBOP were time- and concentration-dependent with an IC50 of 25 nM. IBOP did not affect integrin expression or cytoskeletal morphology of HEC. Since gap junction-mediated intercellular communication increases in migrating HEC, we determined whether IBOP might inhibit coupling or connexin expression in HEC. IBOP reduced the passage of microinjected dyes between HEC by 50%, and the effects of IBOP on migration and tube formation were mimicked by the gap junction inhibitor 18β-glycyrrhetinic acid (1 μM) with a similar time course and efficacy. IBOP (24 h) did not affect the expression or phosphorylation of connexin 43 in whole HEC lysates. Immunohistologic examination of HEC suggested that [BOP may impair functional coupling by altering the cellular distribution of gap junctions, leading to increased connexin 43 internalization. Thus, this finding that TXA2 mimetics can prevent HEC migration and tube formation, possibly by impairing intercellular communication, suggests that antagonizing TXA2 signaling might enhance vascularization of ischemic tissue.

Original languageEnglish (US)
Pages (from-to)35562-35570
Number of pages9
JournalJournal of Biological Chemistry
Volume274
Issue number50
DOIs
StatePublished - Dec 10 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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