期刊
FASEB JOURNAL
卷 31, 期 11, 页码 4946-4958出版社
WILEY
DOI: 10.1096/fj.201700085R
关键词
signaling; GTPase; saliva; Rab5; wound healing
资金
- Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) [1140907, 1140970, 1140697, 11140227]
- Comision Nacional de Investigacion Cientifica y Tecnologica-Fondo de Financiamiento de Centros de Investigacion en Areas Prioritarias (CONICYT-FONDAP) [15130011]
- Fondo de Fomento al Desarrollo Cientifico y Tecnologico (Fondef) [D09E1047]
- Biomedical Research Consortium of Chile (BMRC) [13CTI-21526-P6]
- Instituto Milenio en Inmunologia e Inmunoterapia (IMII) [P09/016-F]
Saliva is a key factor that contributes to the high efficiency of wound healing in the oral mucosa. This is not only attributed to physical cues but also to the presence of specific peptides in the saliva, such as histatins. Histatin-1 is a 38 aa antimicrobial peptide, highly enriched in human saliva, which has been previously reported to promote the migration of oral keratinocytes and fibroblasts in vitro. However, the participation of histatin-1 in other crucial events required for wound healing, such as angiogenesis, is unknown. Here we demonstrate that histatin-1 promotes angiogenesis, as shown in vivo, using the chick chorioallantoic membrane model, and by an in vitro tube formation assay, using both human primary cultured endothelial cells (HUVECs) and the EA. hy926 cell line. Specifically, histatin-1 promoted endothelial cell adhesion and spreading onto fibronectin, as well as endothelial cell migration in the wound closure and Boyden chamber assays. These actions required the activation of the Ras and Rab interactor 2 (RIN2)/Rab5/Rac1 signaling axis, as histatin-1 increased the recruitment of RIN2, a Rab5-guanine nucleotide exchange factor (GEF) to early endosomes, leading to sequential Rab5/Rac1 activation. Accordingly, interfering with either Rab5 or Rac1 activities prevented histatin-1-dependent endothelial cell migration. Finally, by immunodepletion assays, we showed that salivary histatin-1 is required for the promigratory effects of saliva on endothelial cells. In conclusion, we report that salivary histatin-1 is a novel proangiogenic factor that may contribute to oral wound healing.-Torres, P., Diaz, J., Arce, M., Silva, P., Mendoza, P., Lois, P., Molina-Berrios, A., Owen, G. I., Palma, V., Torres, V. A. The salivary peptide histatin-1 promotes endothelial cell adhesion, migration, and angiogenesis.
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