CYP4A/20-HETE regulates ischemia-induced neovascularization via its actions on endothelial progenitor and preexisting endothelial cells.

Authors:
Li Chen
Li Chen
Jiangsu Marine Resources Development Research Institute
China
Samantha Tang
Samantha Tang
University of Sydney
Australia
Frank F Zhang
Frank F Zhang
New York Medical College School of Medicine
Valhalla | United States
Victor Garcia
Victor Garcia
Cincinnati Children's Hospital Medical Center
United States
John R Falck
John R Falck
Medical College of Wisconsin
United States
Michal L Schwartzman
Michal L Schwartzman
New York Medical College
United States
Ali S Arbab
Ali S Arbab
Henry Ford Hospital
United States
Austin M Guo
Austin M Guo
Henry Ford Hospital
United States

Am J Physiol Heart Circ Physiol 2019 Jun 5;316(6):H1468-H1479. Epub 2019 Apr 5.

Department of Pharmacology, New York Medical College, Valhalla, New York.

20-Hydroxyeicosatetraenoic acid (20-HETE) was recently identified as a novel contributor of ischemia-induced neovascularization based on the key observation that pharmacological interferences of CYP4A/20-HETE decrease ischemic neovascularization. The objective of the present study is to examine whether the underlying cellular mechanisms involve endothelial progenitor cells (EPCs) and preexisting endothelial cells (ECs). We found that ischemia leads to a time-dependent increase of cyp4a12 expression and 20-HETE production, which are endothelial in origin, using immunofluorescent microscopy, Western blot analysis, and LC-MS/MS. This is accompanied by increases in the tissue stromal cell-derived factor-1α (SDF-1α) expressions as well as SDF-1α plasma levels, EPC mobilization from bone marrow, and subsequent homing to ischemic tissues. Pharmacological interferences of CYP4A/20-HETE with a 20-HETE synthesis inhibitor, dibromo-dodecenyl-methylsulfimide (DDMS), or a 20-HETE antagonist, -(20-hydroxyeicosa-6(), 15()-dienoyl) glycine (6, 15-20-HEDGE), significantly attenuated these increases. Importantly, we also determined that 20-HETE plays a novel role in maintaining EPC functions and increasing the expression of , , and , which are indicative of increased progenitor cell stemness. Flow cytometric analysis revealed that pharmacological interferences of CYP4A/20-HETE decrease the EPC population in culture, whereas 20-HETE increases the cultured EPC population. Furthermore, ischemia also markedly increased the proliferation, oxidative stress, and ICAM-1 expression in the preexisting EC in the hindlimb gracilis muscles. We found that these increases were markedly negated by DDMS and 6, 15-20-HEDGE. Taken together, CYP4A/20-HETE regulates ischemia-induced compensatory neovascularization via its combined actions on promoting EPC and local preexisting EC responses that are associated with increased neovascularization. CYP4A/20-hydroxyeicosatetraenoic acid (20-HETE) was recently discovered as a novel contributor of ischemia-induced neovascularization. However, the underlying molecular and cellular mechanisms are completely unknown. Here, we show that CYP4A/20-HETE regulates the ischemic neovascularization process via its combined actions on both endothelial progenitor cells (EPCs) and preexisting endothelial cells. Moreover, this is the first study, to the best of our knowledge, that associates CYP4A/20-HETE with EPC differentiation and stemness.

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Source
http://dx.doi.org/10.1152/ajpheart.00690.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620690PMC

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June 2019
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