High Levels of Pigment Epithelium-Derived Factor in Diabetes Impair Wound Healing Through Suppression of Wnt Signaling
High Levels of Pigment Epithelium-Derived Factor in Diabetes Impair Wound Healing Through Suppression of Wnt Signaling
复制标题
糖尿病患者中高水平的色素上皮衍生因子通过抑制 Wnt 信号传导损害伤口愈合
DOI：
10.2337/db14-1111
复制
发表时间：
2015-04-01
期刊：
影响因子：
7.7
通讯作者：
Gao, Guoquan
中科院分区：
文献类型：
--
作者：
Qi, Weiwei;Yang, Chuan;Gao, Guoquan
糖尿病足溃疡（DFU）是糖尿病常见的血管并发症。目前的研究表明，血浆中的色素上皮衍生因子（PEDF）水平升高的2型糖尿病患者DFU和db/db小鼠。为了测试升高的PEDF水平是否有助于糖尿病中的皮肤伤口愈合延迟，在db/db小鼠中用抗PEDF抗体中和内源性PEDF。我们的研究结果表明，PEDF的中和作用加速了糖尿病小鼠伤口愈合，增加了伤口皮肤中的血管生成，并改善了内皮祖细胞（EPCs）的功能和数量。此外，与野生型小鼠相比，PEDF缺陷型小鼠的皮肤基线血流量更高，皮肤微血管密度更高，皮肤厚度增加，循环EPCs的数量和功能改善，伤口愈合加速。PEDF的过表达抑制伤口皮肤中的Wnt信号通路。氯化锂诱导的PEDF相互作用位点下游的Wnt信号转导激活减弱了PEDF对EPCs的抑制作用，并挽救了糖尿病小鼠的伤口愈合缺陷。总之，这些结果表明，循环PEDF水平升高有助于通过抑制Wnt/β-连环蛋白信号传导在血管生成和血管发生过程中受损的伤口愈合。
Diabetic foot ulcer (DFU) caused by impaired wound healing is a common vascular complication of diabetes. The current study revealed that plasma levels of pigment epithelium-derived factor (PEDF) were elevated in type 2 diabetic patients with DFU and in db/db mice. To test whether elevated PEDF levels contribute to skin wound-healing delay in diabetes, endogenous PEDF was neutralized with an anti-PEDF antibody in db/db mice. Our results showed that neutralization of PEDF accelerated wound healing, increased angiogenesis in the wound skin, and improved the functions and numbers of endothelial progenitor cells (EPCs) in the diabetic mice. Further, PEDF-deficient mice showed higher baseline blood flow in the skin, higher density of cutaneous microvessels, increased skin thickness, improved numbers and functions of circulating EPCs, and accelerated wound healing compared with wild-type mice. Overexpression of PEDF suppressed the Wnt signaling pathway in the wound skin. Lithium chloride-induced Wnt signaling activation downstream of the PEDF interaction site attenuated the inhibitory effect of PEDF on EPCs and rescued the wound-healing deficiency in diabetic mice. Taken together, these results suggest that elevated circulating PEDF levels contribute to impaired wound healing in the process of angiogenesis and vasculogenesis through the inhibition of Wnt/-catenin signaling.