Neurovascular factors in wound healing in the foot skin of Type 2 diabetic subjects

Objective Delayed wound healing in diabetic patients without large vessel disease has been attributed to microvascular dysfunction, neuropathy, and abnormal cellular and inflammatory responses. The role of these abnormalities has been examined mainly in animal models. Few studies have been undertaken in diabetic patients and those that have are limited due to analysis in wounds from chronic ulcers. In this study, we quantified the rate of wound healing in relation to skin neurovascular function and structure following a dorsal foot skin biopsy in Type 2 diabetes. Research Design and Methods Twelve healthy controls (C) and 12 Type 2 subjects with neuropathy (D) but without macrovascular disease were studied. We quantified rate of wound healing and related it to skin microvascular function (LDImax), blood vessel density (BVD), small nerve fiber function (LDIflare) and density (NFD), VEGF and its receptor (FLK1) and hypoxia inducible factor (HIF) 1α expression. Results The rate of wound closure was identical between control subjects and diabetic patients despite a significant reduction in maximum hyperemia (LDImax), epidermal and dermal VEGF-A and epidermal and dermal blood vessel VEGFR-2 expression as well as the neurogenic flare response (LDIflare) and dermal nerve fiber density. There was no significant difference in HIF-1α and dermal blood vessel density between control subjects and diabetic patients. Conclusion In conclusion, the results of this study suggest that wound closure in subjects with type 2 diabetes is not delayed despite significant alterations in neurovascular function and structure. 3 Introduction Wound healing is impaired in diabetic patients and has been attributed to both macro and microvascular disease leading to tissue hypoxia, peripheral neuropathy, and abnormal cellular and inflammatory pathways predisposing to infection in foot ulcers (1-4). The molecular basis for these abnormalities has been examined mainly in animal models, which have a limited translational capacity. The loss of protective sensation due to neuropathy and diminished trophic effect by neuropeptide deficiency have been proposed to lead to trauma and increased pressure on the foot skin and a diminished hyperemic response to tissue injury, respectively (5). Furthermore, these alterations may lead acute wounds to advance to chronic wounds with impaired healing (6). More recently, small fiber dysfunction has been shown to be a early feature in patients with Type 2 diabetes and has also been implicated in delayed wound healing (7,8). Moreover, several microvascular abnormalities including a reduced response to tissue injury causing under perfusion, the development of dependent edema …