Caroline Chenu1, Marine Adlanmerini1, Frederic Boudou1, Elodie Chantalat1, Anne-Laure Guihot1, Céline Toutain1, Isabelle Raymond-Letron1, Patricia Vicendo1, Alain-Pierre Gadeau1, Daniel Henrion1, Jean-François Arnal1, Françoise Lenfant2. 1. From the INSERM U1048, Institut de Médecine Moléculaire de Rangueil, CHU Toulouse, Université Toulouse III Paul-Sabatier, France (C.C., M.A., F.B., E.C., C.T., J.-F.A., F.L.); Département d'Anatomie-Pathologique, Ecole Nationale Vétérinaire de Toulouse, France (I.R.-L.); Laboratoire des IMRCP, UMR 5623, Université de Toulouse, Université Paul Sabatier, France (P.V.); INSERM U1034, Université de Bordeaux, Pessac, France (A.-P.G.); and MITOVASC, CARFI, INSERM U1083 and CNRS UMR6214, Université d'Angers, France (A.-L.G., D.H.). 2. From the INSERM U1048, Institut de Médecine Moléculaire de Rangueil, CHU Toulouse, Université Toulouse III Paul-Sabatier, France (C.C., M.A., F.B., E.C., C.T., J.-F.A., F.L.); Département d'Anatomie-Pathologique, Ecole Nationale Vétérinaire de Toulouse, France (I.R.-L.); Laboratoire des IMRCP, UMR 5623, Université de Toulouse, Université Paul Sabatier, France (P.V.); INSERM U1034, Université de Bordeaux, Pessac, France (A.-P.G.); and MITOVASC, CARFI, INSERM U1083 and CNRS UMR6214, Université d'Angers, France (A.-L.G., D.H.). Francoise.Lenfant@inserm.fr.
Abstract
OBJECTIVE: Chronic nonhealing wounds are a substantial medical concern and are associated with morbidity and mortality; thus, new treatment strategies are required. The first step toward personalized/precision medicine in this field is probably in taking sex differences into account. Impaired wound healing is augmented by ischemia, and we previously demonstrated that 17β-estradiol exerts a major preventive effect against ischemia-induced skin flap necrosis in female mice. However, the equivalent effects of testosterone in male mice have not yet been reported. We then investigated the role of steroid hormones in male mice using a skin flap ischemia model. APPROACH AND RESULTS: Castrated male mice developed skin necrosis after ischemia, whereas intact or castrated males treated with testosterone were equally protected. Testosterone can (1) activate the estrogen receptor after its aromatization into 17β-estradiol or (2) be reduced into dihydrotestosterone, a nonaromatizable androgen that activates the androgen receptor. We found that dihydrotestosterone protected castrated wild-type mice by promoting skin revascularization, probably through a direct action on resistance arteries, as evidenced using a complementary model of flow-mediated outward remodeling. 17β-estradiol treatment of castrated male mice also strongly protected them from ischemic necrosis through the activation of estrogen receptor-α by increasing skin revascularization and skin survival. Remarkably, 17β-estradiol improved skin survival with a greater efficiency than dihydrotestosterone. CONCLUSIONS: Testosterone provides males with a strong protection against cutaneous necrosis and acts through both its estrogenic and androgenic derivatives, which have complementary effects on skin survival and revascularization.
OBJECTIVE: Chronic nonhealing wounds are a substantial medical concern and are associated with morbidity and mortality; thus, new treatment strategies are required. The first step toward personalized/precision medicine in this field is probably in taking sex differences into account. Impaired wound healing is augmented by ischemia, and we previously demonstrated that 17β-estradiol exerts a major preventive effect against ischemia-induced skin flap necrosis in female mice. However, the equivalent effects of testosterone in male mice have not yet been reported. We then investigated the role of steroid hormones in male mice using a skin flap ischemia model. APPROACH AND RESULTS: Castrated male mice developed skin necrosis after ischemia, whereas intact or castrated males treated with testosterone were equally protected. Testosterone can (1) activate the estrogen receptor after its aromatization into 17β-estradiol or (2) be reduced into dihydrotestosterone, a nonaromatizable androgen that activates the androgen receptor. We found that dihydrotestosterone protected castrated wild-type mice by promoting skin revascularization, probably through a direct action on resistance arteries, as evidenced using a complementary model of flow-mediated outward remodeling. 17β-estradiol treatment of castrated male mice also strongly protected them from ischemic necrosis through the activation of estrogen receptor-α by increasing skin revascularization and skin survival. Remarkably, 17β-estradiol improved skin survival with a greater efficiency than dihydrotestosterone. CONCLUSIONS:Testosterone provides males with a strong protection against cutaneous necrosis and acts through both its estrogenic and androgenic derivatives, which have complementary effects on skin survival and revascularization.
Authors: Vinícius de Paiva Gonçalves; João Paulo Steffens; Carlos Rossa Junior; Luís Carlos Spolidorio Journal: Inflamm Res Date: 2022-03-30 Impact factor: 4.575
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Chia-Hua Wu; Shayan Mohammadmoradi; Jeff Z Chen; Hisashi Sawada; Alan Daugherty; Hong S Lu Journal: Arterioscler Thromb Vasc Biol Date: 2018-07 Impact factor: 8.311