Prevention of skin flap necrosis by estradiol involves reperfusion of a protected vascular network.
Although 17beta-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 (ERalpha(-/-)) but maintained in chimeric mice reconstituted with ERalpha-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.
Toutain
Céline E
CE
Institut National de la Santé et de la Recherche Médicale, U858, Toulouse, France.
Brouchet
Laurent
L
Raymond-Letron
Isabelle
I
Vicendo
Patricia
P
Bergès
Hortense
H
Favre
Julie
J
Fouque
Marie-José
MJ
Krust
Andrée
A
Schmitt
Anne-Marie
AM
Chambon
Pierre
P
Gourdy
Pierre
P
Arnal
Jean-François
JF
Lenfant
Françoise
F
D000818:Animals; D016026:Bone Marrow Transplantation; D002470:Cell Survival; D062109:Dermatologic Surgical Procedures; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D007511:Ischemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009336:Necrosis; D010052:Ovariectomy; D012039:Regional Blood Flow; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D012867:Skin / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D013524:Surgical Flaps / Q000009:adverse effects*; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors
D004343:Drug Implants; D047628:Estrogen Receptor alpha; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D004958:Estradiol