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.
Pharmacology, Toxicology and Pharmaceutical Science
2
6%
Business, Management and Accounting
1
3%
Other
3
10%
Unknown
4
13%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 15 April 2015.
All research outputs
#21,565,131
of 34,358,242 outputs
Outputs from Arteriosclerosis, Thrombosis, and Vascular Biology (Highwire)
#5,192
of 7,131 outputs
Outputs of similar age
#174,328
of 306,779 outputs
Outputs of similar age from Arteriosclerosis, Thrombosis, and Vascular Biology (Highwire)
#42
of 100 outputs
Altmetric has tracked 34,358,242 research outputs across all sources so far. This one is in the 37th percentile – i.e., 37% of other outputs scored the same or lower than it.
So far Altmetric has tracked 7,131 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 10.1. This one is in the 26th percentile – i.e., 26% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 306,779 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 42nd percentile – i.e., 42% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 100 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 57% of its contemporaries.
