Topical Reformulation of Valsartan for Treatment of Chronic Diabetic Wounds.
Chronic wounds are among the most devastating and difficult to treat consequences of diabetes. Dysregulation of the skin renin-angiotensin system (RAS) is implicated in abnormal wound healing in diabetic and older adults. Given this, we sought to determine the effects of topical reformulations of the angiotensin type 1 receptor blockers (ARB) losartan and valsartan and the angiotensin-converting enzyme (ACE) inhibitor captopril on wound healing in diabetic and aged mice with further validation in older diabetic pigs. Application of 1% valsartan gel compared to other tested formulations and placebo facilitated and significantly accelerated closure time and increased tensile strength in mice, and was validated in the porcine model. 1% Valsartan gel-treated wounds also exhibited higher mitochondrial content, collagen deposition, phosphorylated SMAD2 and 3 and Co-SMAD4, αSMA, CD31, phospho-VEGF receptor 2, and p42/44 MAPK. Knockout of the angiotensin subtype 2 receptors (AT2R) abolished the beneficial effects of ARBs, suggesting a role for AT2R in chronic wound healing.