Activation of GRP78 on endothelial cell membranes by an ADAM15-derived peptide induces angiogenesis

Annat Raiter*, Chana Weiss, Zafrir Bechor, Itzik Ben-Dor, Alexander Battler, Boris Kaplan, Britta Hardy

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Impaired angiogenesis is one of the features of ischemic diseases. We have previously identified, by screening a phage display peptide library, a peptide that induces angiogenesis in endothelial cells under hypoxic conditions by binding the cell's membrane heat shock protein GRP78. Protein data base search identified 4 amino acids (HWRR) of that synthetic peptide present on the ADAM15 metalloprotease domain, a protein considered to be involved in neovascularization. Three peptides were synthesized according to the ADAM15 sequence placing HWRR at different positions. Peptide ADoPep1 exhibited significant angiogenic properties under hypoxic conditions as determined by cell proliferation, migration and tube formation. In a mouse hind limb ischemia model, a single injection of the peptide restored blood perfusion. The identified peptide was found to activate GRP78 on endothelial cell membrane and siRNA directed against the GRP78 mRNA interfered with induction of angiogenesis by the peptide. The peptide binding induced a decrease in heat shock protein GRP78 that is overexpressed under hypoxic conditions. The mechanism of peptide-induced angiogenic activity involves inhibition of apoptosis as well as increased Akt phosphorylation and ERK 1/2 activation. The peptide did not induce VEGF receptor-2 protein synthesis and phosphorylation, suggesting a VEGF-independent mechanism of angiogenesis.

Original languageEnglish
Pages (from-to)399-411
Number of pages13
JournalJournal of Vascular Research
Issue number5
StatePublished - Aug 2010
Externally publishedYes


  • Angiogenesis
  • Endothelial cells
  • HWRR motif
  • Heat shock GRP78 protein
  • Ischemia model


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