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Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy

Nature Medicine volume 6, pages 405–413 (2000)Cite this article

Abstract

Ischemic peripheral neuropathy is a frequent, irreversible complication of lower extremity vascular insufficiency. We investigated whether ischemic peripheral neuropathy could be prevented and/or reversed by gene transfer of an endothelial cell mitogen designed to promote therapeutic angiogenesis. Intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor (VEGF) simultaneously with induction of hindlimb ischemia in rabbits abrogated the substantial decrease in motor and sensory nerve parameters, and nerve function recovered promptly. When gene transfer was administered 10 days after induction of ischemia, nerve function was restored earlier and/or recovered faster than in untreated rabbits. These findings are due in part to enhanced hindlimb perfusion. In addition, however, the demonstration of functional VEGF receptor expression by Schwann cells indicates a direct effect of VEGF on neural integrity as well. These findings thus constitute a new paradigm for the treatment of ischemic peripheral neuropathy.

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Figure 1: Time course of electrophysiologic parameters and calf blood pressure ratio for rabbits with hindlimb ischemia (untreated; black lines and bar; n=10); gene transfer 10 days after induction of ischemia (red dotted lines and red bar; n=10); and gene transfer at time of surgery (blue lines and bar; n=10).
Figure 2: Transverse sections of rabbit common peroneal nerve from an untreated, ischemic hindlimb (Epoxy resin section 1 μm in thickness, stained with toluidine blue).
Figure 3: Transverse section of common peroneal nerve from ischemic hindlimb, injected with 500 μg of phVEGF165 immediately after surgery (at the onset of ischemia).
Figure 4: Effect of rhVEGF165 on primary rat Schwann cell migration in a modified Boyden chamber chemotaxis assay.
Figure 5: Functional VEGF receptor expression in cultured Schwann cells.
Figure 6: VEGF acts as a survival factor for Schwann cells.

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Acknowledgements

This study was supported in part by National Institutes of Health grants HL53354, HL57516, HL60911, the E.L. Wiegand Foundation, and the Peter Lewis Foundation. P.S. is the recipient of an Erwin Schroedinger fellowship grant, provided by the Austrian Ministry of Science.

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Authors and Affiliations

  1. Division of Cardiovascular Research St. Elizabeth's Medical Center–Tufts University School of Medicine, 736 Cambridge Street, Boston, 02135, Massachusetts, USA

    Peter Schratzberger, Gabriele Schratzberger, Marcy Silver, Cynthia Curry, Marianne Kearney, Meredith Magner & Jeffrey M. Isner

  2. Division of Vascular Medicine St. Elizabeth's Medical Center–Tufts University School of Medicine, 736 Cambridge Street, Boston, 02135, Massachusetts, USA

    Cynthia Curry, Marianne Kearney & Jeffrey M. Isner

  3. Division of Neurology, St. Elizabeth's Medical Center–Tufts University School of Medicine, 736 Cambridge Street, Boston, 02135, Massachusetts, USA

    David H. Weinberg & Allan H. Ropper

  4. Department of Pathology Tufts University School of Medicine, 750 Washington Street, Boston, 02111, Massachusetts, USA

    Joseph Alroy

  5. Department of Neuropathology, Tufts University School of Medicine, 750 Washington Street, Boston, 02111, Massachusetts, USA

    Lester S. Adelman

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  1. Peter Schratzberger
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Correspondence to Jeffrey M. Isner.

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Schratzberger, P., Schratzberger, G., Silver, M. et al. Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy . Nat Med 6, 405–413 (2000). https://doi.org/10.1038/74664

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