Evidence map›Paper›PMID 34499621›Full record

ArticleJCI insight2021

Complement-containing small extracellular vesicles from adventitial fibroblasts induce proinflammatory and metabolic reprogramming in macrophages.

Sushil Kumar, Maria G Frid, Hui Zhang, Min Li, Suzette Riddle, R Dale Brown, Subhash Chandra Yadav, Micaela K Roy, Monika E Dzieciatkowska, Angelo D'Alessandro and 2 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in JCI insight, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.

0numbers the graph read from it
0cells of the map it votes in
35citing papers in PubMed
2.7field-weighted citation impact, top 9% of its field
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

35 citing papers in PubMed, 47 citations in OpenAlex.

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  11. Observational
  12. Article
  13. Vascular Remodeling: The Multicellular Mechanisms of Pulmonary Hypertension.International journal of molecular sciences · 2025
    Review
  14. Article
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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

12 authors at 2 institutions in 2 countries.

Sushil KumarCardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Maria G FridCardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Hui ZhangCardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Min LiCardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Suzette RiddleCardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
R Dale BrownCardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Subhash Chandra YadavDepartment of Anatomy, All India Institute of Medical Sciences, New Delhi, India.
Micaela K RoyDepartment of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Monika E DzieciatkowskaDepartment of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Angelo D'AlessandroDepartment of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Kirk C HansenDepartment of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Kurt R StenmarkCardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
University of Colorado Anschutz Medical Campus · USAll India Institute of Medical Sciences · IN

Funding

VRAC and Rho in pulmonary EC proliferationP01HL014985 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI STENMARK, KURT R. · 1985 to 2019
$35.1M
Role of Complement-Driven Pulmonary Vascular Inflammation in PHP01HL152961 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI DELANEY, CASSIDY A · 2020 to 2024
$14.1M
NHLBI NIH HHS P01 HL014985NHLBI NIH HHS P01 HL152961
6 · The paper itself

Abstract

Pulmonary hypertension (PH) is a severe cardiopulmonary disease characterized by complement-dependent, fibroblast-induced perivascular accumulation and proinflammatory activation of macrophages. We hypothesized that, in PH, nanoscale-sized small extracellular vesicles (sEVs), released by perivascular/adventitial fibroblasts, are critical mediators of complement-dependent proinflammatory activation of macrophages. Pulmonary adventitial fibroblasts were isolated from calves with severe PH (PH-Fibs) and age-matched controls (CO-Fibs). PH-Fibs exhibited increased secretion of sEVs, compared with CO-Fibs, and sEV biological activity was tested on mouse and bovine bone marrow-derived macrophages (BMDMs) and showed similar responses. Compared with sEVs derived from CO-Fibs, sEVs derived from PH-Fibs (PH-Fib-sEVs) induced augmented expression of proinflammatory cytokines/chemokines and metabolic genes in BMDMs. Pharmacological blockade of exosome release from PH-Fibs resulted in significant attenuation of proinflammatory activation of BMDMs. "Bottom-up" proteomic analyses revealed significant enrichment of complement and coagulation cascades in PH-Fib-sEVs, including augmented expression of the complement component C3. We therefore examined whether the PH-Fib-sEV-mediated proinflammatory activation of BMDMs was complement C3 dependent. Treatment of PH-Fibs with siC3-RNA significantly attenuated the capacity of PH-Fib-sEVs for proinflammatory activation of BMDMs. PH-Fib-sEVs mediated proglycolytic alterations and complement-dependent activation of macrophages toward a proinflammatory phenotype, as confirmed by metabolomic studies. Thus, fibroblast-released sEVs served as critical mediators of complement-induced perivascular/microenvironmental inflammation in PH.

Indexed as

AnimalsCellular ReprogrammingDisease Models, AnimalExtracellular VesiclesFibroblastsHumansHypertension, PulmonaryMacrophagesMiceCardiovascular diseaseHypertensionInflammationMacrophagesPulmonology

Identifiers

PMID34499621
PMCPMC8663554
OpenAlexW3197371766

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

None linked

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 OpenQuestion graph.