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Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis

Gene Therapy volume 11, pages 302–309 (2004)Cite this article

Abstract

Soluble receptors to vascular endothelial growth factor (VEGF) can inhibit its angiogenic effect. Since angiogenesis is involved in wound repair, we hypothesized that adenovirus-mediated gene transfer of a soluble form of VEGF receptor 2 (Flk-1) would attenuate wound healing in mice. C57Bl/6J and genetically diabetic (db/db) mice (each n=20) received intravenous (i.v.) injections of recombinant adenoviruses (109 PFU) encoding the ligand-binding ectodomain of VEGF receptor 2 (Flk-1) or cDNA encoding the murine IgG2α Fc fragment (each n=10). At 4 days after gene transfer, two full-thickness skin wounds (0.8 cm) were created on the dorsum of each animal. Wound closure was measured over 9–14 days after which wounds were resected for histological analysis. Prior to killing, fluorescent microspheres were systemically injected for quantitation of wound vascularity. Single i.v. injections of adenoviruses encoding soluble Flk-1 significantly decreased wound angiogenesis in both wild-type and diabetic mice. Fluorescence microscopy revealed a 2.0-fold (wild type) and 2.9-fold (diabetic) reduction in wound vascularity in Flk-1-treated animals (p<0.05). Impairment of angiogenesis was confirmed by CD31 immunohistochemistry. Interestingly, despite significant reductions in wound vascularity, wound closure was not grossly delayed. Our data indicates that while VEGF function is essential for optimal wound angiogenesis, it is not required for wound closure.

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Acknowledgements

This work was supported by grants from the the German Research Foundation (Ja 1043/1-1) to JJ, the National Heart, Lung and Blood Institute (R01 HL-58638) to JC, the National Cancer Institute (1 R01 CA95654-01), the Department of Defense (PC010475) and CaP CURE to CK. Dr Kuo is a Burroughs Wellcome Foundation New Investigator in the Pharmacological Sciences and a Kimmel Foundation Scholar in Translational Science. Dr Cooke is an Established Investigator of the American Heart Association.

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Stanford University School of Medicine, CA, USA

    Johannes Jacobi & John P Cooke

  2. Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA

    Betty YY Tam & Calvin J Kuo

  3. Division of Pathology, Stanford University School of Medicine, Stanford, CA, USA

    Uma Sundram

  4. Department of Microbiology and Immunology, Baxter Laboratory of Genetic Pharmacology, Stanford University Medical Center, CA, USA

    Georges von Degenfeld & Helen M Blau

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  1. Johannes Jacobi
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Jacobi, J., Tam, B., Sundram, U. et al. Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis. Gene Ther 11, 302–309 (2004). https://doi.org/10.1038/sj.gt.3302162

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