title: High levels of pigment epithelium-derived factor in diabetes impair wound healing through suppression of Wnt signaling.
abstract: 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/β-catenin signaling.
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Qi
authors.affiliation: Department of Endocrinology, Second Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Che
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Rui
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Zhongxiao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Xuemin
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Ti
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Guangzhou Women and Children's Medical Center, Guangzhou, People's Republic of China.
authors.forename: Xiaoqiong
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Endocrinology, Second Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China gaogq@mail.sysu.edu.cn yangxia@mail.sysu.edu.cn jian-xing-ma@ouhsc.edu hfxyl@163.net.
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China China Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, People's Republic of China gaogq@mail.sysu.edu.cn yangxia@mail.sysu.edu.cn jian-xing-ma@ouhsc.edu hfxyl@163.net.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK gaogq@mail.sysu.edu.cn yangxia@mail.sysu.edu.cn jian-xing-ma@ouhsc.edu hfxyl@163.net.
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China Key Laboratory of Functional Molecules from Marine Microorganisms (Sun Yat-Sen University), Department of Education of Guangdong Province, Guangzhou, People's Republic of China gaogq@mail.sysu.edu.cn yangxia@mail.sysu.edu.cn jian-xing-ma@ouhsc.edu hfxyl@163.net.
authors.forename: Guoquan
authors.initials: G
authors.lastname: Gao
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D017719:Diabetic Foot / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D005136:Eye Proteins / Q000097:blood*; D006801:Humans; D051379:Mice; D009414:Nerve Growth Factors / Q000097:blood*; D015843:Serpins / Q000097:blood*; D012867:Skin / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor