Journal article
Loss of interleukin-21 receptor activation in hypoxic endothelial cells impairs perfusion recovery after hindlimb ischemia
Arteriosclerosis, thrombosis, and vascular biology, Vol.35(5), pp.1218-1225
05/2015
DOI: 10.1161/ATVBAHA.115.305476
PMCID: PMC4865891
PMID: 25838422
Abstract
Surgical hindlimb ischemia (HLI) in mice has become a valuable preclinical model to study peripheral arterial disease. We previously identified that the different phenotypic outcomes after HLI across inbred mouse strains is related to a region on the short arm of mouse chromosome 7. The gene coding the interleukin-21 receptor (IL-21R) lies at the peak of association in this region.
With quantitative real-time polymerase chain reaction, we found that a mouse strain with a greater ability to upregulate IL-21R after HLI had better perfusion recovery than a strain with no upregulation after HLI. Immunofluorescent staining of ischemic hindlimb tissue showed IL-21R expression on endothelial cells (ECs) from C57BL/6 mice. An EC-enriched fraction isolated from ischemic hindlimb muscle showed higher Il-21R levels than an EC-enriched fraction from nonischemic limbs. In vitro, human umbilical vein ECs showed elevated IL-21R expression after hypoxia and serum starvation. Under these conditions, IL-21 treatment increased cell viability, decreased cell apoptosis, and augmented tube formation. In vivo, either knockout Il21r or blocking IL-21 signaling by treating with IL-21R-Fc (fusion protein that blocks IL-21 binding to its receptor) in C57BL/6 mice resulted in less perfusion recovery after HLI. Both in vitro and in vivo modulation of the IL-21/IL-21R axis under hypoxic conditions resulted in increased signal transducer and activator of transcription 3 phosphorylation and a subsequent increase in the B-cell lymphoma leukemia-2/BCL-2-associated X protein ratio.
Our data indicate that IL-21R upregulation and ligand activation in hypoxic ECs may help perfusion recovery by limiting/preventing apoptosis and favoring cell survival and angiogenesis through the signal transducer and activator of transcription 3 pathway.
Details
- Title: Subtitle
- Loss of interleukin-21 receptor activation in hypoxic endothelial cells impairs perfusion recovery after hindlimb ischemia
- Creators
- Tao Wang - University of VirginiaAlexis Cunningham - University of VirginiaAyotunde O Dokun - University of VirginiaSurovi Hazarika - University of VirginiaKevin Houston - University of VirginiaLingdan Chen - University of VirginiaR John Lye - University of VirginiaRosanne Spolski - National Institutes of HealthWarren J Leonard - National Institutes of HealthBrian H Annex - University of Virginia
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.35(5), pp.1218-1225
- DOI
- 10.1161/ATVBAHA.115.305476
- PMID
- 25838422
- PMCID
- PMC4865891
- NLM abbreviation
- Arterioscler Thromb Vasc Biol
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Grant note
- R01 HL121635 / NHLBI NIH HHS R01HL121635 / NHLBI NIH HHS R01HL16455 / NHLBI NIH HHS R01 HL116455 / NHLBI NIH HHS
- Language
- English
- Date published
- 05/2015
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984297595102771
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