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

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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 2014

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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

  • Pharmacology
  • Molecular Medicine

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, J R; Arbab, Ali S.; Scicli, A. Guillermo; Schwartzman, Michal L.; Yang, Jing; Guo, Austin M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 348, No. 3, 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, J R ; Arbab, Ali S. ; 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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AU - Ackerman, Rachel

AU - Saleh, Mohamed

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AU - Kessler, Michael

AU - Mendelowitz, Lawrence G.

AU - Falck, J R

AU - Arbab, Ali S.

AU - Scicli, A. Guillermo

AU - Schwartzman, Michal L.

AU - Yang, Jing

AU - Guo, Austin M.

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