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Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2

Nature Medicine volume 9, pages 604–613 (2003)Cite this article

Abstract

The establishment of functional and stable vascular networks is essential for angiogenic therapy. Here we report that a combination of two angiogenic factors, platelet-derived growth factor (PDGF)-BB and fibroblast growth factor (FGF)-2, synergistically induces vascular networks, which remain stable for more than a year even after depletion of angiogenic factors. In both rat and rabbit ischemic hind limb models, PDGF-BB and FGF-2 together markedly stimulated collateral arteriogenesis after ligation of the femoral artery, with a significant increase in vascularization and improvement in paw blood flow. A possible mechanism of angiogenic synergism between PDGF-BB and FGF-2 involves upregulation of the expression of PDGF receptor (PDGFR)-α and PDGFR-β by FGF-2 in newly formed blood vessels. Our data show that a specific combination of angiogenic factors establishes functional and stable vascular networks, and provides guidance for the ongoing clinical trials of angiogenic factors for the treatment of ischemic diseases.

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Figure 1: Synergistic angiogenesis induced by PDGF-BB and FGF-2.
Figure 2: Blood vessel stability.
Figure 3: Vascular stability after depletion of angiogenic factors.
Figure 4: Histological analysis of corneal neovascularization.
Figure 5: Stimulation of arteriogenesis and improvement of blood perfusion in ischemic rat hind limbs.
Figure 6: Treatment of ischemic rabbit hind limbs and in situ detection of PDGFR-α and PDGFR-βon newly formed blood vessels.

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Acknowledgements

We thank B. Heilborn for technical assistance. This work is supported by research grants from the Human Frontier Science Program, the Swedish Research Council, the Swedish Heart and Lung Foundation, the Swedish Cancer Foundation, the Karolinska Institute Foundation and the Åke Wibergs Foundation. Y.C. is supported by the Swedish Research Council.

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Authors and Affiliations

  1. Laboratory of Angiogenesis Research, Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden

    Renhai Cao, Ebba Bråkenhielm & Yihai Cao

  2. Genetix Pharmaceuticals, Inc., Cambridge, Massachusetts, USA

    Robert Pawliuk & Philippe Leboulch

  3. Department of Vascular Surgery, Karolinska Hospital, Stockholm, Sweden

    David Wariaro & Eric Wahlberg

  4. Department of Medicine, Dartmouth Medical School, Lebanon, New Hampshire, USA

    Mark J. Post

  5. Harvard Medical School and Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Boston, Massachusetts, USA

    Philippe Leboulch

  6. INSERM EMI 0111, Hopital Saint-Louis, Paris, France

    Philippe Leboulch

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  1. Renhai Cao
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Correspondence to Yihai Cao.

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Cao, R., Bråkenhielm, E., Pawliuk, R. et al. Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat Med 9, 604–613 (2003). https://doi.org/10.1038/nm848

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