title: Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice.
abstract: Impaired wound healing is a major source of morbidity in diabetic patients. Poor outcome has, in part, been related to increased inflammation, poor angiogenesis, and deficiencies in extracellular matrix components. Despite the enormous impact of these chronic wounds, effective therapies are lacking. Here, we showed that the topical application of recombinant matricellular protein angiopoietin-like 4 (ANGPTL4) accelerated wound reepithelialization in diabetic mice, in part, by improving angiogenesis. ANGPTL4 expression is markedly elevated upon normal wound injury. In contrast, ANGPTL4 expression remains low throughout the healing period in diabetic wounds. Exogenous ANGPTL4 modulated several regulatory networks involved in cell migration, angiogenesis, and inflammation, as evidenced by an altered gene expression signature. ANGPTL4 influenced the expression profile of endothelial-specific CD31 in diabetic wounds, returning its profile to that observed in wild-type wounds. We showed ANGPTL4-induced nitric oxide production through an integrin/JAK/STAT3-mediated upregulation of inducible nitric oxide synthase (iNOS) expression in wound epithelia, thus revealing a hitherto unknown mechanism by which ANGPTL4 regulated angiogenesis via keratinocyte-to-endothelial-cell communication. These data show that the replacement of ANGPTL4 may be an effective adjunctive or new therapeutic avenue for treating poor healing wounds. The present finding also confirms that therapeutic angiogenesis remains an attractive treatment modality for diabetic wound healing.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Nanyang Drive, Singapore, Singapore.
authors.forename: Han Chung
authors.initials: HC
authors.lastname: Chong
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Nanyang Drive, Singapore, Singapore.
authors.forename: Jeremy Soon Kiat
authors.initials: JS
authors.lastname: Chan
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Nanyang Drive, Singapore, Singapore.
authors.forename: Chi Qin
authors.initials: CQ
authors.lastname: Goh
authors.affiliation: Institute of Molecular and Cell Biology, Proteos, A*STAR, Singapore, Singapore.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Gounko
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, Nanyang Avenue, Singapore, Singapore.
authors.forename: Baiwen
authors.initials: B
authors.lastname: Luo
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Nanyang Drive, Singapore, Singapore.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Nanyang Drive, Singapore, Singapore.
authors.forename: Selin
authors.initials: S
authors.lastname: Foo
authors.affiliation: Tan Tock Seng Hospital, Jalan Tan Tock Seng, Singapore.
authors.forename: Marcus Thien Chong
authors.initials: MT
authors.lastname: Wong
authors.affiliation: School of Materials Science and Engineering, Nanyang Technological University, Nanyang Avenue, Singapore, Singapore.
authors.forename: Cleo
authors.initials: C
authors.lastname: Choong
authors.affiliation: Nutrition, Metabolism and Genomics group, Wageningen Univeristy, Wageningen, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.affiliation: 1] School of Biological Sciences, Nanyang Technological University, Nanyang Drive, Singapore, Singapore [2] Institute of Molecular and Cell Biology, Proteos, A*STAR, Singapore, Singapore.
authors.forename: Nguan Soon
authors.initials: NS
authors.lastname: Tan
mesh_terms: D042682:Angiopoietins / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D002450:Cell Communication; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D062326:Re-Epithelialization; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D042682:Angiopoietins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse