Diabetic wounds represent a medical and economical burden with a high need to develop more efficient therapies.
Estrogens have a positive effect on cutaneous wound healing. Their decreased levels could count for impaired wound healing in elderly. The biological estrogens effects are mediated by two nuclear receptors subtypes (ERα and ERβ) and they were differently implied for the wound healing benefic processes. However, the estrogen effects on diabetic wounds have not yet been studied.
Here, we investigate the role of estrogen receptors subtypes on the wound healing rate in diabetes.
Methods: Diabetes was induced with streptozotocin in knock out for alpha (ERKO) or beta (BERKO) estrogen receptors mice and in wild type controls. Wounds were performed on the dorsum of animals, and evaluated by photos taken every second day. At the end of the experiment, wounds biopsies were analyzed for granulation, dermal regeneration (hematoxilin eosin), angiogenesis (isolectin staining), markers for inflammation and recruitment of endothelial precursor cells (EPC) (qRT-PCR). In vitro, migration and angiogenesis assays were evaluated on primary dermal fibroblasts and endothelial cells in the presence of specific estrogen subtype receptors modulators.
Results: Wound healing rate in diabetic BERKO, but not diabetic ERKO mice was significantly faster than in diabetic controls (50% wound closure at 3.4±0.3 days (P<0.05), 4.5±0.5 days respectively 4.7±0.5 days). This correlated with levels of granulation tissue and with recruitment of EPCs in the wounds of BERKO mice. Agonists for both specific estrogen receptors significantly increased fibroblasts migration rate, while angiogenesis was accelerated only by blocking the beta estrogen receptor.
Conclusion: In diabetes, BERKO mice display an accelerated wound healing when compared to ERKO or control mice. Moreover, beta estrogen receptor inhibition leads to better recruitment of EPC and angiogenesis suggesting the use of specific ER modulators for therapeutic trials.