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

Abstract

Abstract-Although 17␤-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␣ Ϫ/Ϫ ) 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 Ⅲ skin flap model Ⅲ ischemia S kin flaps are frequently used in plastic and reconstructive surgery. However, necrosis represents a major complication that may require secondary surgical interventions, generate multiple infections, and delay future treatments. Necrosis is caused by severe ischemia, resulting from impaired arterial inflow, especially in the distal part of the flap. Therapeutic angiogenesis by local administration of angiogenic growth factors fibroblast growth factor (FGF)-2 1 and vascular endothelial growth factor (VEGF), 2 and a combination of these growth factors, 3 have been successfully tested to enhance blood perfusion in affected tissues, decreasing the extent of flap necrosis. However, the safety of this approach remains controversial, 4 and no efficient therapy is currently available.Estrogens appear to be attractive candidates, because 17␤-estradiol (E2) exerts protective effects in various animal models of cardiac, brain, and hindlimb ischemia 5-7 by favoring angiogenesis, limiting endothelial dysfunction, and exerting inflammatory and antiapoptotic effects. 8,9 In elderly patients, E2 supplementation accelerates cutaneous wound healing. 10 The mechanisms underlying these changes involve an increase in transforming growth factor (TGF)-␤ 1 secretion 11 but also inhibition of the loca...

Endothelial Estrogen Receptor α Plays an Essential Role in the Coronary and Myocardial Protective Effects of Estradiol in Ischemia/Reperfusion

“…1,9,18 In particular, the protective action of E2 in cardiac I/R is largely demonstrated, but the cellular targets involved in this protection were still undefined. The present data demonstrated that the long-term activation of the endothelial ER␣ by E2 elicits both coronary endothelial and myocardial protective effects after cardiac I/R, and this does not require the concomitant activation of ER␣ expression in the hematopoietic compartment.…”

“…5 Researchers have extensively documented the protective role of ER␣ in various situations, such as the acceleration of reendothelialization, 6 atheroma, 7,8 and the prevention of ischemia-induced skin necrosis. 9 Thus, our second aim was to determine whether ER␣ mediates the coronary protective effect of E2. Despite the fact that ER␤ took part in the E2 protection of ischemic myocardium, 3,10 we chose to focus our study on ER␣, considering its major role in endothelium.…”

Oestrogen promotes healing in a bacterial LPS model of delayed cutaneous wound repair

“…44 Indeed, the beneficial effects of oestrogen on healing have been demonstrated across a range of pathological skin wound models, including aged and ovariectomised mice, 46,47 type I 65 and type 2 diabetes 66 and the skin flap ischemia model, 67 where oestrogen has been shown to dampen the local immune response, promote keratinocyte migration and proliferation and induce fibroblast-mediated matrix deposition. 46 In addition, oestrogenic effects on thermal injury have been well studied, for example, in the brain, where reduced inflammation and apoptosis are linked to lower levels of DAMPs.…”

Key Role of Estrogens and Endothelial Estrogen Receptor α in Blood Flow–Mediated Remodeling of Resistance Arteries

“…Three-month-old female Wistar rats (Charles River, L'Arbresles, France) were ovariectomized (OVX) 17 and 1 week later submitted to surgery to increase blood flow in 1 mesenteric artery. 18 Three consecutive first-order arteries were used.…”

“…17 The latter mice were compared with their littermate wildtype (WT) controls (Tie2Cre(−)ERα). All mice were on a C57BL/6J background.…”