Calcitriol promotes proangiogenic molecules in keratinocytes in a diabetic foot ulcer model

•The present study shows that angiogenic molecules such as ANG is downregulated in diabetic foot ulcers (DFU).•Although there is a hypoxic environment in DFUs, the hypoxic transcription factor HIF1a downregulated in DFU.•Vitamin D3 induces the production of ANG and HIF1A expression promoting endothe...

Full description

Saved in:
Bibliographic Details
Published inThe Journal of steroid biochemistry and molecular biology Vol. 174; pp. 303 - 311
Main Authors Trujillo, Valentin, Marín-Luevano, Paulina, González-Curiel, Irma, Rodríguez-Carlos, Adrián, Ramírez-Reyes, Maira, Layseca-Espinosa, Esther, Enciso-Moreno, José A., Díaz, Lorenza, Rivas-Santiago, Bruno
Format Journal Article
LanguageEnglish
Published England Elsevier Ltd 01.11.2017
Elsevier BV
Subjects
Online AccessGet full text

Cover

Loading…
More Information
Summary:•The present study shows that angiogenic molecules such as ANG is downregulated in diabetic foot ulcers (DFU).•Although there is a hypoxic environment in DFUs, the hypoxic transcription factor HIF1a downregulated in DFU.•Vitamin D3 induces the production of ANG and HIF1A expression promoting endothelial and keratinocyte cell migration. Foot ulceration is one of the most common and complex sequelae of diabetes mellitus, generally posing a therapeutic challenge due to poor healing responses and high rates of complications, including peripheral vascular disease, ischemia and infections. Calcitriol, the most active vitamin D metabolite, induces antimicrobial peptides production in keratinocytes from diabetic foot ulcers (DFU); however, little is known about its effects on angiogenic factors in this pathology. Herein we aimed at studying whether calcitriol induces angiogenic molecules in keratinocytes under normoxic and hypoxic conditions, and if these molecules are able to improve cell migration in vitro. Evaluation of DFU samples by immunohistochemistry showed increased VEGF and decreased angiogenin and HIF-1α expression compared to controls, suggesting an altered pattern of angiogenic factors in DFU. Interestingly, incubation of keratinocytes with calcitriol significantly upregulated VEGFA, HIF-1α and angiogenin gene expression, while the resulting cell culture media stimulated both endothelial cells and keratinocytes migration in an in vitro wound closure assay under a normoxic environment (p<0.05). Moreover, the culture media of calcitriol-treated keratinocytes stimulated cell migration in a similar extent as exogenous VEGF or EGF in endothelial and keratinocytes cells. These results suggest that the altered profile of angiogenic molecules in DFU might be improved by local or systemic treatment with calcitriol under normoxic conditions, which could probably be achieved with hyperbaric oxygen therapy. Given that calcitriol not only augments proangiogenic factors but also induces antimicrobial peptides expression, this hormone should be further investigated in clinical trials of DFU.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0960-0760
1879-1220
DOI:10.1016/j.jsbmb.2017.10.013