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.

Resolvin E1 Reverses Experimental Periodontitis and Dysbiosis

“…The expression of these genes was down-regulated by RvE1 treatment. The expression of the genes associated with vascularization as well as angiogenesis ( Angptl4 ) (77) and superoxide production as well as neutrophil migration ( Rac2 ) (78) were increased in disease and decreased upon resolution This was also observed in a human experimental gingivitis study (ANGPTL1) (79) and human periodontitis-affected gingiva (RAC2) (80). The gene, Cxcl1 , was significantly downregulated following RvE1 application in both prevention and treatment studies (Figs.…”

Fibrinogen-Related Proteins in Tissue Repair: How a Unique Domain with a Common Structure Controls Diverse Aspects of Wound Healing

“…Thus, cross talk between keratinocytes and epithelial cells may prove to be a unique therapeutic target in the improvement of angiogenesis in diabetic wounds. 86 Tenascin-C is expressed by keratinocytes 87 and fibroblasts in dermal wound healing during the phases of reepithelialization and granulation tissue formation. 88 However, tenascin-C knockout mice show very minor defects in wound healing exhibiting temporarily reduced fibronectin in the granulation tissue.…”

Inhibition of Janus kinase-2 signalling pathway ameliorates portal hypertensive syndrome in partial portal hypertensive and liver cirrhosis rats

“…JAK2, the most conserved isoform of the JAK family, functions upstream of STAT3 in JAK/STAT signalling. Studies have shown that JAK2/STAT3 signalling plays an important role in fibrogenesis, angiogenesis and immune/inflammatory reactions by regulating factors such as VEGF, TGF-␤, eNOS and inducible nitric oxide synthase (iNOS) in numerous diseases [8][9][10][11]. However, the function of JAK2A/STAT3 signalling in portal hypertension remains unclear.…”