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, John R. Falck, Ali Syed Arbab, A. Guillermo Scicli, Michal L. Schwartzman, Jing Yang, Austin M. Guo

Research output: Contribution to journalArticle

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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 1 2014
Externally publishedYes

Fingerprint

Vascular Endothelial Growth Factor A
Cytochrome P-450 CYP4A
Endothelial Progenitor Cells
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Very Late Antigen Receptors
Cell Proliferation
Integrin alpha4beta1
Chemokine Receptors
Neutralizing Antibodies
Fibronectins
Cell Adhesion
Cytochrome P-450 Enzyme System
Proteins
Endothelial Cells
Gene Expression
Messenger RNA
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

20-HETE regulates the angiogenic functions of human endothelial progenitor cells and contributes to angiogenesis in vivo. / Chen, Li; Ackerman, Rachel; Saleh, Mohamed; Gotlinger, Katherine H.; Kessler, Michael; Mendelowitz, Lawrence G.; Falck, John R.; Arbab, Ali Syed; Scicli, A. Guillermo; Schwartzman, Michal L.; Yang, Jing; Guo, Austin M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 348, No. 3, 01.03.2014, p. 442-451.

Research output: Contribution to journalArticle

Chen, L, Ackerman, R, Saleh, M, Gotlinger, KH, Kessler, M, Mendelowitz, LG, Falck, JR, Arbab, AS, Scicli, AG, Schwartzman, ML, Yang, J & Guo, AM 2014, '20-HETE regulates the angiogenic functions of human endothelial progenitor cells and contributes to angiogenesis in vivo', Journal of Pharmacology and Experimental Therapeutics, vol. 348, no. 3, pp. 442-451. https://doi.org/10.1124/jpet.113.210120
Chen, Li ; Ackerman, Rachel ; Saleh, Mohamed ; Gotlinger, Katherine H. ; Kessler, Michael ; Mendelowitz, Lawrence G. ; Falck, John R. ; Arbab, Ali Syed ; Scicli, A. Guillermo ; Schwartzman, Michal L. ; Yang, Jing ; Guo, Austin M. / 20-HETE regulates the angiogenic functions of human endothelial progenitor cells and contributes to angiogenesis in vivo. In: Journal of Pharmacology and Experimental Therapeutics. 2014 ; Vol. 348, No. 3. pp. 442-451.
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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.",
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