Peptide-matrix-mediated gene transfer of an oxygen-insensitive hypoxia-inducible factor-1α variant for local induction of angiogenesis

Diana Trentin, Heike Hall, Sandra Wechsler, Jeffrey A. Hubbell

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Abstract

Hypoxia-inducible factor (HIF) constitutes a target in therapeutic angiogenesis. HIF-1α functions as a sensor of hypoxia and induces expression of vascular endothelial growth factor (VEGF), which then induces angiogenesis. To explore the potential of HIF-1α gene therapy in stimulating wound healing, we delivered a gene encoding a stabilized form of HIF-1α, lacking the oxygen-sensitive degradation domain, namely HIF-1αΔODD, by using a previously characterized peptide-based gene delivery vector in fibrin as a surgical matrix. The peptide vector consisted of multiple domains: (i) A cysteine-flanked lysine hexamer provided DNA interactions that were stable extracellularly but destabilized intracellularly after reduction of the formed disulfide bonds. This DNA-binding domain was fused to either (ii) a fibrin-binding peptide for entrapment within the matrix or (iii) a nuclear localization sequence for efficient nuclear targeting. The HIF-1αΔODD gene was expressed and translocated to the nucleus under normoxic conditions, leading to up-regulation of vascular endothelial growth factor (VEGF)-A165 mRNA and protein levels in vitro. When the peptide-DNA nanoparticles entrapped in fibrin matrices were applied to full-thickness dermal wounds in the mouse (10 μg per wound in 30 μl of fibrin), angiogenesis was increased comparably strongly to that induced by VEGF-A165 protein (1.25 μg per wound in 30 μl of fibrin). However, the maturity of the vessels induced by HIF-1αΔODD was significantly higher than that induced by VEGF-A165 protein, as shown by stabilization of the neovessels with smooth muscle. Nonviral, local administration of this potent angiogenesis-inducing gene by using this peptide vector represents a powerful approach in tissue engineering and therapeutic angiogenesis.

Original languageEnglish (US)
Pages (from-to)2506-2511
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number8
DOIs
StatePublished - Feb 21 2006

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Keywords

  • Fibrin
  • Gene delivery
  • Nonviral vector
  • Polycation

ASJC Scopus subject areas

  • Genetics
  • General

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