title: Testosterone Prevents Cutaneous Ischemia and Necrosis in Males Through Complementary Estrogenic and Androgenic Actions.
abstract: 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.
  
  
  
  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.
  
  
  
  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.affiliation: 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.).
authors.forename: Caroline
authors.initials: C
authors.lastname: Chenu
authors.affiliation: 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.).
authors.forename: Marine
authors.initials: M
authors.lastname: Adlanmerini
authors.affiliation: 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.).
authors.forename: Frederic
authors.initials: F
authors.lastname: Boudou
authors.affiliation: 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.).
authors.forename: Elodie
authors.initials: E
authors.lastname: Chantalat
authors.affiliation: 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.).
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Guihot
authors.affiliation: 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.).
authors.forename: Céline
authors.initials: C
authors.lastname: Toutain
authors.affiliation: 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.).
authors.forename: Isabelle
authors.initials: I
authors.lastname: Raymond-Letron
authors.affiliation: 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.).
authors.forename: Patricia
authors.initials: P
authors.lastname: Vicendo
authors.affiliation: 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.).
authors.forename: Alain-Pierre
authors.initials: AP
authors.lastname: Gadeau
authors.affiliation: 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.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.affiliation: 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.).
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
authors.affiliation: 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.
authors.forename: Françoise
authors.initials: F
authors.lastname: Lenfant
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000172:deficiency / Q000235:genetics; D020249:Hormone Replacement Therapy; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009919:Orchiectomy; D017208:Rats, Wistar; D012867:Skin / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013524:Surgical Flaps / Q000098:blood supply* / Q000473:pathology; D013997:Time Factors; D014022:Tissue Survival / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D016207:Cytokines; D047628:Estrogen Receptor alpha; D013196:Dihydrotestosterone; D004958:Estradiol
keywords: androgens; dihydrotestosterone; estradiol; ischemia; testosterone