The salivary peptide histatin-1 promotes endothelial cell adhesion, migration, and angiogenesis

FASEB J. 2017 Nov;31(11):4946-4958. doi: 10.1096/fj.201700085R. Epub 2017 Jul 27.


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., Díaz, J., Arce, M., Silva, P., Mendoza, P., Lois, P., Molina-Berríos, A., Owen, G. I., Palma, V., Torres, V. A. The salivary peptide histatin-1 promotes endothelial cell adhesion, migration, and angiogenesis.

Keywords: GTPase; Rab5; saliva; signaling; wound healing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / metabolism
  • Angiogenesis Inducing Agents / pharmacology*
  • Carrier Proteins / metabolism
  • Cell Adhesion / drug effects
  • Cell Line
  • Cell Movement / drug effects*
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Guanine Nucleotide Exchange Factors / metabolism
  • Histatins / metabolism
  • Histatins / pharmacology*
  • Humans
  • Mouth Mucosa / injuries
  • Mouth Mucosa / metabolism
  • Mouth Mucosa / pathology
  • Neovascularization, Physiologic / drug effects*
  • Salivary Proteins and Peptides / metabolism
  • Salivary Proteins and Peptides / pharmacology*
  • Wound Healing / drug effects
  • rab5 GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein / metabolism


  • Angiogenesis Inducing Agents
  • Carrier Proteins
  • Guanine Nucleotide Exchange Factors
  • Histatins
  • RAC1 protein, human
  • RIN2 protein, human
  • Salivary Proteins and Peptides
  • HTN1 protein, human
  • RAB5C protein, human
  • rab5 GTP-Binding Proteins
  • rac1 GTP-Binding Protein