Abstract 14370: The Atypical Neurotrophin Receptor P75NTR Impairs Angiogenesis and Healing of Diabetic and Ischemic Skin Wounds
Background: Diabetes-induced vasculopathy severely impairs the healing of ischemic cutaneous wounds, leading to more limb amputations in diabetic patients. We already provided evidences that: 1). type-1 diabetes induces p75NTR expression in endothelial cells (ECs) of intra-scapular skin wounds, 2) p75NTR impairs EC survival and functions; 3) p75NTR is responsible for diabetes-induced defective post-ischemic angiogenesis in limb muscles.
Methods and Results: To study the role of p75NTR in the healing of ischemic and diabetic limb wounds, unilateral limb ischemia and a full excisional skin wound (5-mm-wide) on the ipsilateral calf were induced in streptozotocin-induced diabetic and non-diabetic p75NTR−/− and p75NTR+/+ mice. Wound areas were measured (by calliper) immediately after punching and 3 days and wound closure ratio was calculated. At 3 days, wound capillary density (CD31 staining) was measured and wound gene profiling (Agilent 4x44k arrays), was performed and analyzed by cluster enrichment analysis (DAVID 6.7). Non-diabetic p75NTR−/− and p75NTR+/+ mice exhibited similar wound closure rate and capillary density (P=NS for both comparisons). Diabetes reduced wound closure and capillary density in diabetic p75NTR+/+ mice (58.43±7.8% vs. 71.43±5.1%, p<0.05 and 212±26 vs 281±16 capillaries/mm2, p<0.01, vs. non-diabetic p75NTR+/+). Diabetic p75NTR−/− mice exhibited accelerate wound closure (71.76±6.8%) and increased angiogenesis (261±11 capillaries/mm2) (p<0.05 for both comparisons vs diabetic p75NTR+/+). We identified a set of 59 genes differentially expressed in diabetic vs non-diabetic p75NTR+/+ mice and whose expression was normal in diabetic p75NTR−/− mice. These genes were clustered for their functional annotation, showing an enrichment for angiogenesis-associated genes (12.9% on total genes, p<0.01), including Factor VII, PKC-ε, ITGB2 and sFRP1 and for cytokine-associated genes (11.5% on total genes, p<0.01), such as IL-1 receptor, CXCR4, CXCL10 and Pf4.
Conclusions: p75NTR impairs healing of diabetic and ischemic limb wounds. We have identified set of genes that might be potential targets for therapeutic angiogenesis in diabetic ulcers.
- © 2010 by American Heart Association, Inc.