Estrogen deprivation is considered responsible for many age-related processes, including poor wound healing. Guided by previous observations that estradiol accelerates re-epithelialization through estrogen receptor (ER)-β, in the present study, we examined whether selective ER agonists [4,4′,4″-(4-propyl [1H] pyrazole-1,3,5-triyl)-trisphenol (PPT), ER-α agonist; 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), ER-β agonist] affect the expression of basic proliferation and differentiation markers (Ki-67, keratin-10, -14 and -19, galectin-1 and Sox-2) of keratinocytes using HaCaT cells. In parallel, ovariectomized rats were treated daily with an ER modulator, and wound tissue was removed 21 days after wounding and routinely processed for basic histological analysis. Our results revealed that the HaCaT keratinocytes expressed both ER-α and -β, and thus are well-suited for studying the effects of ER agonists on epidermal regeneration. The activation of ER-α produced a protein expression pattern similar to that observed in the control culture, with a moderate expression of Ki-67 being observed. However, the activation of ER-β led to an increase in cell proliferation and keratin-19 expression, as well as a decrease in galectin-1 expression. Fittingly, in rat wounds treated with the ER-β agonist (DPN), epidermal regeneration was accelerated. In the present study, we provide information on the mechanisms through which estrogens affect the expression patterns of selected markers, thus modulating keratinocyte proliferation and differentiation; in addition, we demonstrate that the pharmacological activation of ER-α and -β has a direct impact on wound healing.

We demonstrated that PL aqueous extract improves skin wound healing in rats. However, further research need to be performed to find optimal therapeutic concentration, and exact underlying mechanism prior obtained results may be introduced into the clinical practice.

Selective estrogen receptor modulators (SERMs) have been developed to achieve beneficial effects of estrogens while minimizing their side effects. In this context, we decided to evaluate the protective effect of genistein, a natural SERM, on skin flap viability in rats and in a series of in vitro experiments on endothelial cells (migration, proliferation, antioxidant properties, and gene expression profiling following genistein treatment). Our results showed that administration of genistein increased skin flap viability, but importantly, the difference is only significant when treatment is started 3 days prior the flap surgery. Based on our in vitro experiments, it may be hypothesized that the underlying mechanism may rather by mediated by increasing SOD activity and Bcl-2 expression. The gene expression profiling further revealed 9 up-regulated genes (angiogenesis/inflammation promoting: CTGF, CXCL5, IL-6, ITGB3, MMP-14, and VEGF-A; angiogenesis inhibiting: COL18A1, TIMP-2, and TIMP-3). In conclusion, we observed a protective effect of genistein on skin flap viability which could be potentially applied in plastic surgery to women undergoing a reconstructive and/or plastic intervention. Nevertheless, further research is needed to explain the exact underlying mechanism and to find the optimal treatment protocol.

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