title: A novel strategy to enhance angiogenesis in vivo using the small VEGF-binding peptide PR1P.
abstract: Therapeutic angiogenesis is an experimental frontier in vascular biology that seeks to deliver angiogenic growth factors to ischemic or injured tissues to promote targeted formation of new blood vessels as an alternative approach to surgical revascularization procedures. Vascular endothelial growth factor (VEGF) is a potent angiogenic signal protein that is locally upregulated at sites of tissue injury. However, therapies aimed at increasing VEGF levels experimentally by injecting VEGF gene or protein failed to improve outcomes in human trials in part due to its short half-life and systemic toxicity. We recently designed a novel 12-amino acid peptide (PR1P) whose sequence was derived from an extracellular VEGF-binding domain of the pro-angiogenic glycoprotein prominin-1. In this study, we characterized the molecular binding properties of this novel potential therapeutic for targeted angiogenesis and provided the foundation for its use as an angiogenic molecule that can potentiate endogenous VEGF. We showed that PR1P bound VEGF directly and enhanced VEGF binding to endothelial cells and to VEGF receptors VEGFR2 and neuropilin-1. PR1P increased angiogenesis in the murine corneal micropocket assay when combined with VEGF, but had no activity without added VEGF. In addition, PR1P also enhanced angiogenesis in murine choroidal neovascularization and wound-healing models and augmented reperfusion in a murine hind-limb ischemia model. Together our data suggest that PR1P enhanced angiogenesis by potentiating the activity of endogenous VEGF. In so doing, this novel therapy takes advantage of endogenous VEGF gradients generated in injured tissues and may improve the efficacy of and avoid systemic toxicity seen with previous VEGF therapies.
authors.affiliation: Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. avner.adini@childrens.harvard.edu.|Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. avner.adini@childrens.harvard.edu.
authors.forename: Avner
authors.initials: A
authors.lastname: Adini
authors.affiliation: Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Irit
authors.initials: I
authors.lastname: Adini
authors.affiliation: Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Zai-Long
authors.initials: ZL
authors.lastname: Chi
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, AB, Canada.
authors.forename: Ratmir
authors.initials: R
authors.lastname: Derda
authors.affiliation: Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Birsner
authors.affiliation: Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.|Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Matthews
authors.affiliation: Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.|Department of Ophthalmology, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: D'Amato
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D005260:Female; D006801:Humans; D007511:Ischemia / Q000473:pathology; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D010477:Perfusion; D011485:Protein Binding / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D043925:Angiogenesis Inducing Agents; C000626790:PR1P peptide; D010446:Peptide Fragments; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A
keywords: Angiogenesis; PR1P; Peptide; Pro-angiogenesis therapy; VEGF; prominin-1