20-HETE regulates the angiogenic functions of human endothelial progenitor cells and contributes to angiogenesis in vivo

Li Chen, Rachel Ackerman, Mohamed Saleh, Katherine H. Gotlinger, Michael Kessler, Lawrence G. Mendelowitz, J R Falck, Ali S. Arbab, A. Guillermo Scicli, Michal L. Schwartzman, Jing Yang, Austin M. Guo

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Circulating endothelial progenitor cells (EPC) contribute to postnatal neovascularization. We identified the cytochrome P450 4A/ F-20- hydroxyeicosatetraenoic acid (CYP4A/F-20-HETE) system as a novel regulator of EPC functions associated with angiogenesis in vitro. Here, we explored cellular mechanisms by which 20- HETE regulates EPC angiogenic functions and assessed its contribution to EPC-mediated angiogenesis in vivo. Results showed that both hypoxia and vascular endothelial growth factor (VEGF) induce CYP4A11 gene and protein expression (the predominant 20-HETE synthases in human EPC), and this is accompanied by an increase in 20-HETE production by 1.4- and 1.8-fold, respectively, compared with the control levels. Additional studies demonstrated that 20-HETE and VEGF have a synergistic effect on EPC proliferation, whereas 20-HETE antagonist 20- HEDGE or VEGF-neutralizing antibody negated 20-HETE- or VEGF-induced proliferation, respectively. These findings are consistent with the presence of a positive feedback regulation on EPC proliferation between the 20-HETE and the VEGF pathways. Furthermore, we found that 20-HETE induced EPC adhesion to fibronectin and endothelial cell monolayer by 40 ± 5.6 and 67 ± 10%, respectively, which was accompanied by a rapid induction of very late antigen-4 and chemokine receptor type 4 mRNA and protein expression. Basal and 20-HETEstimulated increases in adhesion were negated by the inhibition of the CYP4A-20-HETE system. Lastly, EPC increased angiogenesis in vivo by 3.660.2-fold using the Matrigel plug angiogenesis assay, and these increases were markedly reduced by the local inhibition of 20-HETE system. These results strengthened the notion that 20-HETE regulates the angiogenic functions of EPC in vitro and EPC-mediated angiogenesis in vivo.

Original languageEnglish (US)
Pages (from-to)442-451
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume348
Issue number3
DOIs
StatePublished - Mar 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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