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Mechanisms Underlying the Antifibrotic Potential of Estradiol for Vocal Fold Fibrosis
Author(s) -
Ozawa Satomi,
Mukudai Shigeyuki,
Sugiyama Yoichiro,
Branski Ryan C.,
Hirano Shigeru
Publication year - 2021
Publication title -
the laryngoscope
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.181
H-Index - 148
eISSN - 1531-4995
pISSN - 0023-852X
DOI - 10.1002/lary.29355
Subject(s) - estrogen receptor , endocrinology , medicine , gper , fibrosis , estrogen , receptor , smad , transforming growth factor , estrogen receptor alpha , immunostaining , signal transduction , biology , immunohistochemistry , microbiology and biotechnology , cancer , breast cancer
Objectives/Hypothesis Vocal fold fibrosis remains a significant clinical challenge. Estrogens, steroid hormones predominantly responsible for secondary sexual characteristics in women, have been shown to alter wound healing and limit fibrosis, but the effects on vocal fold fibrosis are unknown. We sought to elucidate the expression of estrogen receptors and the effects of estrogens on TGF‐β1 signaling in rat vocal fold fibroblasts (VFFs). Study Design In vitro. Methods VFFs were isolated from 10‐week‐old, male Sprague–Dawley rats, and estrogen receptor alpha (ERα) and G protein‐coupled receptor 30 (GPR30) were examined via immunostaining and quantitative polymerase chain reaction (qPCR). VFFs were treated with estradiol (E2, 10 −7 , 10 −8 or 10 −9 M) ± transforming growth factor beta 1 (TGF‐β1, 10 ng/mL). ICI 182,780 (ICI, 10 −7 M) or G36 (10 −7 M) were employed as antagonists of ERα or GPR30, respectively. qPCR was employed to determine estrogen receptor‐mediated effects of E2 on genes related to fibrosis. Results ERα and GPR30 were expressed in VFFs at both the protein and the mRNA levels. E2 (10 −7 M) did not alter Smad3 , Smad7 , Acta2 mRNA, or extracellular matrix related genes. However, the combination of E2 (10 −8 M) and TGF‐β1 significantly increased Smad7 ( P = .03) and decreased Col1a1 ( P = .04) compared to TGF‐β1 alone; this response was negated by the combination of ICI and G36 ( P = .009). Conclusions E2 regulated TGF‐β1/Smad signaling via estrogen receptors in VFFs. These findings provide insight into potential mechanisms of estrogens on vocal fold injury with the goal of enhanced therapeutics for vocal fold fibrosis. Level of Evidence NA Laryngoscope , 131:2285–2291, 2021