Hypoxia regulates the expression of extracellular matrix associated proteins in equine dermal fibroblasts via HIF1.
Abstract: Exuberant granulation tissue (EGT), a fibrotic healing disorder resembling the human keloid, occurs almost exclusively in limb wounds of horses and may be caused in part by a relative state of hypoxia within the wound. Objective: The objectives of this study were therefore to (1) assess the effects of hypoxia on equine dermal fibroblast (EDF) proliferation and apoptosis, (2) study the effects of hypoxia on the expression of key extracellular matrix (ECM) associated proteins and determine if such effects are dependent on hypoxia-inducible factor (HIF), and (3) determine if EDFs from the body or limb respond differently to hypoxia. Methods: EDFs were isolated and cultured from skin from body or limb under normoxic or hypoxic conditions for up to 7days. Results: Hypoxia significantly stimulated EDF proliferation, but had no effect on cell survival. The hypoxia-mimetic agent CoCl(2) up-regulated COL1A1 expression and down-regulated MMP2 expression, suggesting an increase in ECM synthesis and a decrease in turnover. Both regulatory effects were inhibited by the addition of echinomycin, indicating that they are mediated by the transcriptional regulatory activity of HIF. No differences were observed between EDFs originating from body or limb for any effect of hypoxia or CoCl(2), suggesting that EGT development does not depend on intrinsic properties of limb fibroblasts. Conclusions: We conclude that hypoxia regulates ECM remodeling via HIF1 in EDFs, and that this may be an important determinant in the pathogenesis of equine EGT.
Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
Publication Date: 2011-09-29 PubMed ID: 21999945DOI: 10.1016/j.jdermsci.2011.09.006Google Scholar: Lookup
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- Journal Article
Summary
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This study investigates how low-oxygen conditions (hypoxia) can affect the behaviour of horse skin cells (dermal fibroblasts), particularly their production of extracellular matrix proteins, and whether these effects can be linked to a common healing disorder in horses. The influence of these conditions on cell propagation and programmed cell death was also examined.
Objectives and Methods
- The research aimed to evaluate the impact of low oxygen availability on the proliferation and death of equine dermal fibroblasts (cells that produce connective tissue proteins).
- Researchers also examined if hypoxia can alter the expression of key proteins related to extracellular matrix (ECM, a three-dimensional network of extracellular macromolecules such as collagen, enzymes, and glycoproteins), and whether Hypoxia-inducible factor (HIF, a regulatory protein that responds to low oxygen conditions) is involved in this regulation.
- Another objective was to determine whether EDFs from different areas of the horse’s body react differently to hypoxia.
- In the methodology, EDFs were isolated from the skin of horses, both from the body and limb, and cultured under normal and low-oxygen conditions for up to a week.
Results
- The study found that hypoxic conditions significantly increased the propagation of EDFs, but had no impact on their survival.
- Another significant finding is that a hypoxia-mimicking agent CoCl(2) elevated the expression of COL1A1 (a collagen gene) and reduced the expression of MMP2 (an enzyme involved in ECM degradation), suggesting increased ECM synthesis and decreased turnover – changes indicative of tissue remodeling.
- The study showed that these changes were inhibited by the addition of echinomycin, supporting the conclusion that they were driven by HIF’s regulation on gene expression.
- The reactions of EDFs to hypoxia or CoCl(2) didn’t show any noticeable difference depending on whether they came from the body or the limb of the horse. This suggests that the onset of the healing disorder EGT is not associated with any inherent properties of limb fibroblasts.
Conclusion
- The researchers concluded that low-oxygen conditions affect the remodelling of ECM through the regulatory action of HIF1 in EDFs. This finding may be crucial in understanding the causes of Exuberant Granulation Tissue (EGT), a common healing disorder in horses that’s likened to keloid in humans.
Cite This Article
APA
Deschene K, Céleste C, Boerboom D, Theoret CL.
(2011).
Hypoxia regulates the expression of extracellular matrix associated proteins in equine dermal fibroblasts via HIF1.
J Dermatol Sci, 65(1), 12-18.
https://doi.org/10.1016/j.jdermsci.2011.09.006 Publication
Researcher Affiliations
- Université de Montréal, Département de biomédecine vétérinaire, Canada.
MeSH Terms
- Animals
- Apoptosis
- Cell Proliferation
- Cell Survival
- Extracellular Matrix / metabolism
- Fibroblasts / metabolism
- Horses
- Humans
- Hypoxia
- Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
- Keloid / metabolism
- Models, Biological
- Skin / metabolism
- Time Factors
- Wound Healing
Citations
This article has been cited 16 times.- Boizot J, Minville-Walz M, Reinhardt DP, Bouschbacher M, Sommer P, Sigaudo-Roussel D, Debret R. FBN2 Silencing Recapitulates Hypoxic Conditions and Induces Elastic Fiber Impairment in Human Dermal Fibroblasts.. Int J Mol Sci 2022 Feb 5;23(3).
- Otto S, Michler JK, Dhein S, Mülling CKW. Development of a constant pressure perfused ex vivo model of the equine larynx.. PLoS One 2021;16(5):e0251530.
- Cequier A, Sanz C, Rodellar C, Barrachina L. The Usefulness of Mesenchymal Stem Cells beyond the Musculoskeletal System in Horses.. Animals (Basel) 2021 Mar 25;11(4).
- de Castro RVG, Pieri NCG, Fantinato Neto P, Grizendi BM, Dória RGS, Meirelles FV, Smith LC, Garcia JM, Bressan FF. In Vitro Induction of Pluripotency from Equine Fibroblasts in 20% or 5% Oxygen.. Stem Cells Int 2020;2020:8814989.
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