20-HETE contributes to ischemia-induced angiogenesis

Li Chen, Gregory Joseph, Frank F. Zhang, Huyen Nguyen, Houli Jiang, Katherine H. Gotlinger, J R Falck, Jing Yang, Michal L. Schwartzman, Austin M. Guo

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Angiogenesis is an important adaptation for recovery from peripheral ischemia. Here, we determined whether 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemia-induced angiogenesis and assessed its underlying molecular and cellular mechanisms using a mouse hindlimb-ischemia angiogenesis model. Hindlimb blood flow was measured by Laser Doppler Perfusion Imaging and microvessel density was determined by CD31 and tomato lectin staining. We found that systemic and local administration of a 20-HETE synthesis inhibitor, DDMS, or a 20-HETE antagonist, 6,15-20-HEDGE significantly reduced blood flow recovery and microvessel formation in response to ischemia. 20-HETE production, measured by LC/MS/MS, was markedly increased in ischemic muscles (91. ±. 11 vs. 8. ±. 2. pg/mg in controls), which was associated with prominent upregulation of the 20-HETE synthase, CYP4A12. Immunofluorescence co-localized increased CYP4A12 expression in response to ischemia to CD31-positive EC in the ischemic hindlimb microvessels. We further showed that ischemia increased HIF-1α, VEGF, and VEGFR2 expression in gracilis muscles and that these increases were negated by DDMS and 6,15-20-HEDGE. Lastly, we showed that ERK1/2 of MAPK is a component of 20-HETE regulated ischemic angiogenesis. Taken together, these data indicate that 20-HETE is a critical contributor of ischemia-induced angiogenesis in vivo.

Original languageEnglish (US)
JournalVascular Pharmacology
DOIs
StateAccepted/In press - Dec 22 2015

Fingerprint

Ischemia
Hindlimb
Microvessels
Perfusion Imaging
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Vascular Endothelial Growth Factor A
Fluorescent Antibody Technique
Lasers
Up-Regulation
Staining and Labeling
Muscles
DDMS

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Physiology

Cite this

Chen, L., Joseph, G., Zhang, F. F., Nguyen, H., Jiang, H., Gotlinger, K. H., ... Guo, A. M. (Accepted/In press). 20-HETE contributes to ischemia-induced angiogenesis. Vascular Pharmacology. https://doi.org/10.1016/j.vph.2016.04.002

20-HETE contributes to ischemia-induced angiogenesis. / Chen, Li; Joseph, Gregory; Zhang, Frank F.; Nguyen, Huyen; Jiang, Houli; Gotlinger, Katherine H.; Falck, J R; Yang, Jing; Schwartzman, Michal L.; Guo, Austin M.

In: Vascular Pharmacology, 22.12.2015.

Research output: Contribution to journalArticle

Chen, L, Joseph, G, Zhang, FF, Nguyen, H, Jiang, H, Gotlinger, KH, Falck, JR, Yang, J, Schwartzman, ML & Guo, AM 2015, '20-HETE contributes to ischemia-induced angiogenesis', Vascular Pharmacology. https://doi.org/10.1016/j.vph.2016.04.002
Chen L, Joseph G, Zhang FF, Nguyen H, Jiang H, Gotlinger KH et al. 20-HETE contributes to ischemia-induced angiogenesis. Vascular Pharmacology. 2015 Dec 22. https://doi.org/10.1016/j.vph.2016.04.002
Chen, Li ; Joseph, Gregory ; Zhang, Frank F. ; Nguyen, Huyen ; Jiang, Houli ; Gotlinger, Katherine H. ; Falck, J R ; Yang, Jing ; Schwartzman, Michal L. ; Guo, Austin M. / 20-HETE contributes to ischemia-induced angiogenesis. In: Vascular Pharmacology. 2015.
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