Effects of calcitriol on random skin flap survival in rats

Random skin flap transplantation is used frequently in plastic surgery1. However, distal flap necrosis remains challenging. Although flap design and surgical techniques have improved over the years, the length-to-width ratio cannot be >1.5-2:1, limiting the clinical applications of such flaps. Previous studies found that inadequate blood supply2, inflammatory reactions3, and oxidative stress4 are three important factors contributing to flap necrosis. Calcitriol (C27H44O3), also known as “1,25-dihydroxyvitamin D3”, exerts many functions associated with bone calcium metabolism and plays a key role in osteoporosis. However, calcitriol has recently been shown to exhibit various other bioactivities. For example, it increases vascular endothelial growth factor (VEGF) expression by binding to a vitamin D response element in the VEGF promotor5. Moreover, VEGF levels in vascular endothelial cells are specifically affected; the cells are stimulated to proliferate and regenerate, promoting angiopoiesis6. Calcitriol has also recently been shown to exert anti-inflammatory effects in a model of diabetic nephropathy7. Sezgin et al.8 showed that 1,25-dihydroxyvitamin D3 reduced oxidative stress status in a model of renal ischemia-reperfusion injury. It has been demonstrated that calcitriol stimulates autophagy9, which relieves oxidative stress10. Moreover, autophagy is a process whereby cells degrade cytosolic macromolecules and organelles in lysosomes, and is thus generally considered to be a survival tactic protecting against stress (e.g., starvation, pro-oxidant conditions)11. Hence, we hypothesized that calcitriol might enhance the survival of random skin flaps. The anti-inflammatory properties of calcitriol, together with its ability to accelerate vascularization, suppress oxidative stress, and induce autophagy, should be helpful in this context. We investigated whether calcitriol exerted such effects in a random skin flap model, via histological and protein analyses.