17β-Estradiol Inhibits Wound Healing in Male Mice via Estrogen Receptor-α

Gilliver, Stephen C.; Emmerson, Elaine; Campbell, Laura; Chambon, Pierre; Hardman, Matthew J.; Ashcroft, Gillian S.

doi:10.2353/ajpath.2010.090432

Cited by 31 publications

(21 citation statements)

References 48 publications

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“…The low levels of STAT3 bound to the miR‐7 promoter, in this study, may therefore have an alternative role to transcriptional transactivation of miR‐7; a mechanism for which should be elucidated in future research. Also of interest would be defining the active ER involved, as both ERα and ERβ were identified to associate with the miR‐7 promoter; however, each was reported to have different roles in cell function and wound healing (Gilliver et al ., 2010). …”

Section: Discussionmentioning

confidence: 99%

17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation

et al. 2016

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SummaryAge‐related defects in fibroblast differentiation and functionality were previously shown to be associated with impaired hyaluronan (HA) synthase 2 (HAS2) and epidermal growth factor receptor (EGFR) function, as a result of upregulated microRNA‐7 (miR‐7) expression. In aging fibroblasts, inhibiting miR‐7 prevented the dysregulation of the HA‐mediated CD44/EGFR signaling pathway. Here, we investigated transcriptional upregulation of miR‐7 and implicated the age‐associated over‐activation of JAK/STAT1 as a primary candidate. STAT1 binding sites were identified on the putative miR‐7 promoter and stimulation of fibroblasts with the inflammatory cytokine, interferon‐γ (IFN‐γ), significantly increased miR‐7 transcriptional activity and resulted in upregulated miR‐7 and loss of EGFR. Additionally, we demonstrated a role for the anti‐inflammatory steroid, 17β‐estradiol (E2), in the attenuation of miR‐7 expression. E2 stimulation promoted estrogen receptor (ER) interactions with the miR‐7 putative promoter and suppressed miR‐7 expression. E2 also attenuated STAT1 expression and activity. Furthermore, treatments with E2 restored fibroblast functionality, including proliferation, migration and differentiation, key events in effective wound healing. In light of our findings, we propose that the regulation of miR‐7 by pro‐ and anti‐inflammatory mediators plays a wider role than previously thought. The modulation of fibroblast functions and ultimately wound healing by miR‐7 activators or inhibitors could provide realistic targets for the restoration of chronic wound healing capabilities in the elderly.

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Section: Discussionmentioning

confidence: 99%

17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation

et al. 2016

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“…Indeed, in male hyperlipidemic analbuminemic rats, estradiol supplementation accelerates the development of renal disease by promoting proteinuria and GSI (11). Supplementation of estradiol in castrated male MF-1 mice slows and delays epithelialization in wound healing (7). Thus, estrogens appear to exert opposing effects in diabetic males and females; however, the mechanisms by which these opposing effects are mediated remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of estradiol synthesis attenuates renal injury in male streptozotocin-induced diabetic rats

Manigrasso

Sawyer

Marbury

et al. 2011

American Journal of Physiology-Renal Physiology

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We previously showed that the male streptozotocin (STZ)-induced diabetic rat exhibits decreased circulating testosterone and increased estradiol levels. While supplementation with dihydrotestosterone is partially renoprotective, the aim of the present study was to examine whether inhibition of estradiol synthesis, by blocking the aromatization of testosterone to estradiol using an aromatase inhibitor, can also prevent diabetes-associated renal injury. The study was performed on male Sprague-Dawley nondiabetic, STZ-induced diabetic, and STZ-induced diabetic rats treated with 0.15 mg/kg of anastrozole, an aromatase inhibitor (Da) for 12 wk. Treatment with anastrozole reduced diabetes-associated increases in plasma estradiol by 39% and increased plasma testosterone levels by 187%. Anastrozole treatment also attenuated urine albumin excretion by 42%, glomerulosclerosis by 30%, tubulointerstitial fibrosis by 32%, along with a decrease in the density of renal cortical CD68-positive cells by 50%, and protein expression of transforming growth factor-β by 20%, collagen type IV by 29%, tumor necrosis factor-α by 28%, and interleukin-6 by 25%. Anastrozole also increased podocin protein expression by 18%. We conclude that blocking estradiol synthesis in male STZ-induced diabetic rats is renoprotective.

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“…However, Gilliver et al. (39) showed that oestradiol did not influence the expression of MMP‐2 in isolated macrophages but showed its in vivo effects on MMP release, which is probably regulated indirectly. Similarly, we showed that both tested ER agonists increased MMP‐2 and MMP‐9 expression but not activity in HUVECs in vitro .…”

Section: Discussionmentioning

confidence: 99%

ER‐α agonist induces conversion of fibroblasts into myofibroblasts, while ER‐β agonist increases ECM production and wound tensile strength of healing skin wounds in ovariectomised rats

Novotný

Vasilenko

Varinská

et al. 2011

Experimental Dermatology

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Oestrogen deprivation is one of the major factors responsible for many age-related processes, including poor wound healing in women. Previously, it has been shown that oestrogens have a modulatory effect in different wound-healing models. Therefore, in this study, the effect of selective oestrogen receptor (ER) agonists (PPT - ER-α agonist, DPN - ER-β agonist) on excisional and incisional wound-healing models was compared in ovariectomised rats in vivo as well as on human dermal fibroblasts (HDF) and human umbilical endothelial cells (HUVEC) in vitro. In the in vivo study, 4 months after either ovariectomy or sham ovariectomy, Sprague-Dawley rats were randomly divided into four groups and subjected to two incisional and excisional wounds: (i) control - sham operated, vehicle-treated; (ii) ovariectomised, vehicle-treated; (iii) ovariectomised, PPT treated; (iv) ovariectomised, DPN treated. In the in vitro study, HDFs and HUVECs were used. After treatment with ER agonists, cells were processed for immunocytochemistry and gelatin zymography. Our study shows that stimulation of ER-α leads to the differentiation of fibroblasts into myofibroblasts both in vivo and in vitro. On the other hand, the formation of extracellular matrix was more prominent, and wound tensile strength (TS) was increased when ER-β was stimulated. In contrast, stimulation of ER-α led to a more prominent increase in the expression of MMP-2 and decrease in wound TS. New information is presented in this investigation concerning oestrogen replacement therapy (ERT) in different wound-healing models. This study demonstrates that the ERT should be both wound and receptor-type specific.

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17β-Estradiol Inhibits Wound Healing in Male Mice via Estrogen Receptor-α

Cited by 31 publications

References 48 publications

17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation

17β-estradiol ameliorates age-associated loss of fibroblast function by attenuating IFN-γ/STAT1-dependent miR-7 upregulation

Inhibition of estradiol synthesis attenuates renal injury in male streptozotocin-induced diabetic rats

ER‐α agonist induces conversion of fibroblasts into myofibroblasts, while ER‐β agonist increases ECM production and wound tensile strength of healing skin wounds in ovariectomised rats

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