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PloS one2018; 13(2); e0192746; doi: 10.1371/journal.pone.0192746

Species-specific regulation of angiogenesis by glucocorticoids reveals contrasting effects on inflammatory and angiogenic pathways.

Abstract: Glucocorticoids are potent inhibitors of angiogenesis in the rodent in vivo and in vitro but the mechanism by which this occurs has not been determined. Administration of glucocorticoids is used to treat a number of conditions in horses but the angiogenic response of equine vessels to glucocorticoids and, therefore, the potential role of glucocorticoids in pathogenesis and treatment of equine disease, is unknown. This study addressed the hypothesis that glucocorticoids would be angiostatic both in equine and murine blood vessels.The mouse aortic ring model of angiogenesis was adapted to assess the effects of cortisol in equine vessels. Vessel rings were cultured under basal conditions or exposed to: foetal bovine serum (FBS; 3%); cortisol (600 nM), cortisol (600nM) plus FBS (3%), cortisol (600nM) plus either the glucocorticoid receptor antagonist RU486 or the mineralocorticoid receptor antagonist spironolactone. In murine aortae cortisol inhibited and FBS stimulated new vessel growth. In contrast, in equine blood vessels FBS alone had no effect but cortisol alone, or in combination with FBS, dramatically increased new vessel growth compared with controls. This effect was blocked by glucocorticoid receptor antagonism but not by mineralocorticoid antagonism. The transcriptomes of murine and equine angiogenesis demonstrated cortisol-induced down-regulation of inflammatory pathways in both species but up-regulation of pro-angiogenic pathways selectively in the horse. Genes up-regulated in the horse and down-regulated in mice were associated with the extracellular matrix. These data call into question our understanding of glucocorticoids as angiostatic in every species and may be of clinical relevance in the horse.
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Publication Date: 2018-02-15 PubMed ID: 29447208PubMed Central: PMC5813970DOI: 10.1371/journal.pone.0192746Google Scholar: Lookup
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  • Journal Article
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  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research investigates the effect of glucocorticoids, a class of steroid hormones, on blood vessel growth (angiogenesis) in horses and rodents. Unlike rodents, where these hormones suppress new blood vessel growth, in horses they surprisingly stimulate angiogenesis, challenging our previous understanding of glucocorticoids’ role on angiogenesis.

Research Methodology

  • The experiment involved comparing the angiogenic responses of vessels from mice and horses to glucocorticoids.
  • The researchers adapted the mouse aortic ring model to assess cortisol’s (a form of glucocorticoid) effects on equine vessels. They cultured vessel rings under basal conditions or exposed them to: fetal bovine serum (FBS; 3%); cortisol (600 nM); cortisol (600nM) plus FBS (3%); or cortisol (600nM) plus either the glucocorticoid receptor antagonist RU486 or the mineralocorticoid receptor antagonist spironolactone.

Findings

  • In murine (rodent) aortae, cortisol inhibited while FBS stimulated new vessel growth.
  • However, in equine (horse) aortae, FBS had no effect, but cortisol alone, or combined with FBS, dramatically increased new vessel growth compared to controls. This growth was blocked when a glucocorticoid receptor antagonist was added, but not when a mineralocorticoid antagonist was used.

Further Analysis

  • On analyzing the transcriptomes of murine and equine angiogenesis, they found that cortisol down-regulated inflammatory pathways in both species.
  • Nevertheless, it up-regulated pro-angiogenic pathways selectively in the horse. The up-regulated genes in horses were associated with the extracellular matrix and were down-regulated in mice.

Implications

  • The findings of this study challenge the assumption that glucocorticoids inhibit angiogenesis in all species.
  • This could have clinical relevance in the treatment of equine diseases where glucocorticoids are used, as in certain cases, they could potentially contribute to disease progression and may complicate treatment response.

Cite This Article

APA
Morgan R, Keen J, Halligan D, O'Callaghan A, Andrew R, Livingstone D, Abernethie A, Maltese G, Walker B, Hadoke P. (2018). Species-specific regulation of angiogenesis by glucocorticoids reveals contrasting effects on inflammatory and angiogenic pathways. PLoS One, 13(2), e0192746. https://doi.org/10.1371/journal.pone.0192746

Publication

PloS one
ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 13
Issue: 2
Pages: e0192746
PII: e0192746

Researcher Affiliations

Morgan, Ruth
  • University/ BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
  • Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom.
Keen, John
  • Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom.
Halligan, Daniel
  • Fios Genomics Ltd, Nine Edinburgh Bioquarter, Edinburgh, United Kingdom.
O'Callaghan, Alan
  • Fios Genomics Ltd, Nine Edinburgh Bioquarter, Edinburgh, United Kingdom.
Andrew, Ruth
  • University/ BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Livingstone, Dawn
  • University/ BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Abernethie, Amber
  • University/ BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Maltese, Giorgia
  • University/ BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Walker, Brian
  • University/ BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
Hadoke, Patrick
  • University/ BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.

MeSH Terms

  • Angiogenesis Inhibitors
  • Animals
  • Blood Vessels / drug effects
  • Blood Vessels / metabolism
  • Female
  • Gene Expression Profiling
  • High-Throughput Nucleotide Sequencing
  • Horse Diseases / physiopathology
  • Horses
  • Hydrocortisone / pharmacology
  • Inflammation / metabolism
  • Male
  • Metabolic Networks and Pathways / drug effects
  • Mice
  • Mifepristone / pharmacology
  • Neovascularization, Pathologic / prevention & control
  • Real-Time Polymerase Chain Reaction
  • Species Specificity
  • Transcriptome

Grant Funding

  • RG/11/4/28734 / British Heart Foundation

Conflict of Interest Statement

Authors DH and AO are employed by FIOS Genomics Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The remaining authors have declared that no competing interests exist.

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Citations

This article has been cited 5 times.
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