Topical valsartan may help heal wounds in people with diabetes. Chronic wounds are wounds that fail to progress through the normal phases of healing and are often thought to stall in the inflammatory phase. These nonhealing wounds represent an enormous burden to patients and society. In patients with diabetes mellitus foot ulcers often result in amputations and early demise. Despite decades of research, treatments fail to cure more than a third of wounds, and innovative solutions are needed. Angiotensin receptor blockers have long been used to safely reduce blood pressure, but could these agents increase the "healing pressure"? Abadir et al. leveraged previous results that suggested that the renin angiotensin system (RAS) is locally dysregulated in skin of diabetic rats. Dysregulation is hypothesized to lead to poor healing by delaying the reversal of angiotensin receptor (ATR) balance between the type 1 and 2 isoforms (AT1R and AT2R, respectively). Normally, AT1R is highly expressed early in healing, creating a prohealing inflammatory environment. Later in the presence of AT2R, proliferative and remodeling phases occur. The investigators hypothesized that blocking the ATR at the right moment toward the "end" of the inflammatory phase would accelerate wound healing and also improve scar quality. In a series of experiments using diabetic mouse and aged diabetic pig models, they found 1% valsartan gel most effective for healing wounds compared to (i) placebo, (ii) other ATR blockers, (iii) other valsartan doses, and (iv) angiotensin converting enzyme blockade. Specifically, compared with placebo, valsartan resulted in faster healing and stronger scars. Morphologically, the wounds demonstrated a healthier appearing wound bed due to increased wound perfusion. The ability to achieve a clean and granulating wound bed could be important as an adjuvant to deploying advanced wound techniques, such as grafting. Importantly, treatment of wounds with 1% valsartan gel delayed healing in AT2R knockout mice, suggesting a pivotal role for the AT2R in healing. This innovative approach appears promising especially given that many RAS modulating agents are already in use. Interestingly, higher angiotensin receptor blocker doses and angiotensin converting enzyme inhibitors did not have a similar effect, suggesting that more studies are needed to better characterize the effect of these agents on the healing pathway. The ability to regenerate collagen in aged skin suggests age-related skin fragility may be reversed and may prove useful in other diseases. Observations in animal models do not always translate to patients; therefore, careful study in human models and patients are needed.
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