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(Circulation Research. 2009;104:245.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Prevention of Skin Flap Necrosis by Estradiol Involves Reperfusion of a Protected Vascular Network

Céline E. Toutain, Laurent Brouchet^*, Isabelle Raymond-Letron^*, Patricia Vicendo, Hortense Bergès, Julie Favre, Marie-José Fouque, Andrée Krust, Anne-Marie Schmitt, Pierre Chambon, Pierre Gourdy, Jean-François Arnal, Françoise Lenfant

From Institut National de la Santé et de la Recherche Médicale (INSERM), U858, Toulouse (C.E.T., L.B., H.B., J.F., M.J.F., P.G., J.F.A., F.L.); Université Toulouse III Paul Sabatier, Institut de Médecine Moléculaire de Rangueil, IFR31, Toulouse (C.T., H.B., J.B., M.J.F., P.G., J.F.A., F.L.); Centre Hospitalier Universitaire de Toulouse, Explorations Fonctionnelles Physiologiques, Toulouse (J.F.A.); Département d’Anatomie Pathologique, Ecole Nationale Vétérinaire de Toulouse, Toulouse (I.R.L.); Université Mixte 5623 au centre National de la Recherche Scientifique, Université Toulouse III Paul Sabatier (P.V.); Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, Collège de France, Illkirch (A.K., P.C.); Pierre Fabre Dermocosmétique, Centre de Recherche sur la Peau et les Epitheliums de Revêtement (A.M.S.); France.

Correspondence to Françoise Lenfant, INSERM U858, CHU Rangueil, BP 84225, 31 432 Toulouse Cedex 4, France. E-mail Francoise.Lenfant{at}inserm.fr

Although 17β-estradiol (E2) is protective in experimental models of myocardial and brain ischemia, its effect on skin ischemia remains unknown. Here, we assessed the protective effect of E2 in a mouse model of skin ischemia, mimicking the surgery of skin flaps. Whereas necrosis appeared in the half portion of the skin flap within 1 week after surgery in ovariectomized mice, it was reduced up to 10-fold when mice were pretreated with E2, at least 3 days before the surgery. The beneficial effect of E2 appeared to be attributable to an increase in skin survival, revealed by measuring viability of ex vivo explants and enhancement of the antiapoptotic Bcl-2 protein expression in vivo. This protective effect on the skin contributed to the protection of the vascular network and facilitated reperfusion, which was found to be accelerated in ovariectomized E2-treated mice, whereas hemorrhages were observed in untreated mice. E2 also increased expression of fibroblast growth factor-2 isoforms in the skin and circulating vascular endothelial growth factor in the serum. Finally, this protective effect of E2 was abolished in estrogen receptor–deficient mice (ER^–/–) but maintained in chimeric mice reconstituted with ER-deficient bone marrow, indicating dispensable action of E2 in bone marrow–derived cells. This protective effect of E2 was mimicked by treatment with tamoxifen, a selective estrogen receptor modulator. In conclusion, we have demonstrated for the first time that E2 exerts a major preventive effect of skin flap necrosis through a prevention of ischemic-induced skin lesions, including those of the vascular network, which contributes to accelerate the reperfusion of the skin flap.

Key Words: estradiol • skin flap model • ischemia

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