Evidence map›Paper›PMID 40640841›Full record

ArticleCardiovascular diabetology2025

Muscle-specific miR-499-5p delivered by small extracellular vesicles impairs endothelial function and ischemic hindlimb recovery in diabetic mice.

Zhongjian Cheng, May M Truongcao, Vandana Mallaredy, Maria Cimini, Charan Thej, Darukeshwara Joladarashi, Carolina Gonzalez, Cindy Benedict, Suresh K Verma, Venkata Naga Srikanth Garikipati and 1 more

Abstract read
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In one paragraph

Article in Cardiovascular diabetology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Review
  2. Review
  3. TheNon-coding RNA · 2025
    Article
  4. Therapeutic Potential of Modulating Gene-MicroRNA Crosstalk in Burn Injury.International journal of molecular sciences · 2025
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Zhongjian ChengAging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA, 19140, USA. zjcheng@temple.edu.
May M TruongcaoAging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA, 19140, USA.
Vandana MallaredyAging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA, 19140, USA.
Maria CiminiAging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA, 19140, USA.
Charan ThejAging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA, 19140, USA.
Darukeshwara JoladarashiAging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA, 19140, USA.
Carolina GonzalezAging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA, 19140, USA.
Cindy BenedictAging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA, 19140, USA.
Suresh K VermaDepartment of Medicine-Cardiovascular Disease, The University of Alabama at Birmingham, 703 19th South Street, Birmingham, AL, 35233, USA.
Venkata Naga Srikanth GarikipatiAging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA, 19140, USA.
Raj KishoreAging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, 3500 Broad Street, Philadelphia, PA, 19140, USA. raj.kishore@temple.edu.

Funding

Project 3P01HL134608 · TEMPLE UNIV OF THE COMMONWEALTH · 2025 to 2025
$2.4M
Restoration of myocardial reparative function of diabetic progenitor cells by epigenetic modulationR01HL143892 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI Raj Kishore · 2021 to 2023
$1.7M
MyomiR-499, Exosomes and Endothelial and Endothelial Progenitor Cells dysfunction in DiabetesR01HL169405 · TEMPLE UNIV OF THE COMMONWEALTH · 2025 to 2025
$617k
American Heart Association 17GRNT33660941 20TPA35460003National Institutes of Health, United State HL143892, HL147841, HL169405, and HL134608NHLBI NIH HHS P01 HL134608NHLBI NIH HHS R01 HL143892NHLBI NIH HHS R01 HL169405
6 · The paper itself

Abstract

backgroundEmerging evidence suggests that skeletal muscle cells (SKMC) play critical roles in the defective angiogenic response in diabetic critical limb ischemia. However, the molecular mechanisms linking skeletal muscle to impaired angiogenic properties of endothelial cells (EC) remain unidentified. The current study investigates how muscle-specific miR-499-5p may impair EC function in diabetic ischemic limbs.

methodsEight-week-old, male C57BL/6 J, db/ + and db/db mice were employed. Hind limb ischemia was established by unilateral ligation of the left femoral artery, and blood flow recovery was monitored using Laser Doppler perfusion imaging (LDPI). ECs and SKMCs were isolated from sham or ischemic hind limbs (IHL). SKMC-derived small extracellular vesicles (SKMC-sEVs) were isolated from the culture medium of SKMCs by ultra-centrifugation.

resultsmiR-499-5p level was markedly increased in SKMCs and unexpectedly in ECs from hindlimb of db/db mice. Ischemic injury further enhanced miR-499-5p levels in ECs from IHL of db/db mice. Angiogenic activity was reduced in ECs from IHL of db/db mice and in miR-499-5p-overexpressing ECs. Intramuscular injection of lentiviral-anti-miR-499-5p improved blood perfusion and angiogenesis in IHL of db/db mice. Mechanistically, we found that diabetic SKMC sEVs carried high levels of miR-499-5p and transferred miR-499-5p to ECs. Intramuscular injection of diabetic SKMC-sEVs repressed IHL recovery in wildtype mice. Blocking sEV biosynthesis/release by GW4869 markedly improved neovascularization and blood perfusion in IHL of db/db mice. We identified that SRY (Sex-Determining Region Y)-Box 6 (SOX6) is a direct downstream target of miR-499-5p. Silencing of SOX6 suppressed release of proangiogenic factors from ECs. Targeted reduction of miR-499-5p significantly enhanced SOX6 levels in ECs from IHL of db/db mice. Finally, overexpression of SOX6 improved the angiogenic property of ECs from IHL of db/db mice.

conclusionsSKMC-sEV-mediated transfer of myo-miR-499-5p and subsequent suppression of SOX6 plays a critical role in diabetes-impaired neovascularization in IHL of db/db mice. Targeting miR-499-5p-mediated pathogenic communication between SKMCs and ECs may be a novel therapeutic avenue for critical limb ischemia in diabetic patients.

Indexed as

Diabetes Mellitus, ExperimentalEndothelial CellsExtracellular VesiclesHindlimbIschemiaMicroRNAsMuscle, SkeletalNeovascularization, PhysiologicAnimalsCells, CulturedDisease Models, AnimalMaleMiceMice, Inbred C57BLRecovery of FunctionRegional Blood FlowMicroRNAsMIRN499 microRNA, mouseDiabetesEndothelial cell dysfunctionIschemic hindlimbmiR-499-5pSkeletal muscle derived-small extracellular vesicles

Identifiers

PMID40640841
PMCPMC12243233

What Socratic holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.