The role of actively released fibrin-conjugated VEGF for VEGF receptor 2 gene activation and the enhancement of angiogenesis

Martin Ehrbar, Steffen M. Zeisberger, George P. Raeber, Jeffrey A. Hubbell, Christian Schnell, Andreas H. Zisch

Research output: Contribution to journalArticle

99 Scopus citations

Abstract

A major challenge for therapeutic delivery of angiogenic agents such as vascular endothelial growth factor (VEGF) is to achieve sustained, low dose signaling leading to durable neovessel formation. To this end, we recently created a variant of VEGF121, TG-VEGF121 that directly binds to fibrin and gets released locally in proteolysis-triggered manner. Here we combined noninvasive biophotonic monitoring of VEGF receptor 2 gene activation in transgenic VEGFR2-luc mice and histomorphometry to compare endothelial activation and long-term neovascularization by actively released TG-VEGF121 versus passively released, diffusible wild-type VEGF121 in subcutaneous fibrin implants. Monitoring in real-time over 3 weeks of luciferase signal driven by the VEGFR2 promoter revealed endothelial activation in skin exposed to wild-type VEGF121, but no detectable elevation over fibrin alone by TG-VEGF121. Histology at 3 weeks, however, demonstrated that TG-VEGF121 promoted vessel growth significantly more effectively and reliably than wild-type VEGF121. The majority of vessels surviving to 3 weeks contained stabilizing smooth muscle cells. Yet, by 6 weeks, no extra vessels induced by exogenous VEGF were left. In conclusion, release of fibrin-conjugated variant TG-VEGF121 elicited lower VEGFR2-luc activation than wild-type VEGF121 yet significantly more vascularization. In the absence of true physiological demand, even stabilized vessels are ultimately regressed.

Original languageEnglish (US)
Pages (from-to)1720-1729
Number of pages10
JournalBiomaterials
Volume29
Issue number11
DOIs
StatePublished - Apr 1 2008

Keywords

  • Biomimetic materials
  • Fibrin
  • Therapeutic angiogenesis
  • Vascular endothelial growth factor
  • VEGF receptor 2 gene activation

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering

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