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Targeting endogenous platelet-derived growth factor B-chain by adenovirus-mediated gene transfer potently inhibits in vivo smooth muscle proliferation after arterial injury

Gene Therapy volume 6, pages 956–965 (1999)Cite this article

Abstract

Platelet-derived growth factor (PDGF), especially its B chain, has been implicated in the pathogenesis of vascular proliferative disorders such as atherosclerosis and restenosis after angioplasty. We constructed a replication-deficient recombinant adenovirus containing the gene encoding the extracellular region of PDGF β-receptor (PDGFXR) that binds PDGF-B chain and acts as its antagonist. The administration into balloon-injured rat carotid arteries of an adenovirus containing the Escherichia coli lacZ gene as a marker gene at 5 days after injury markedly facilitated efficacy of gene transfer, as compared with its administration immediately after injury. Adenovirus-mediated gene transfer of PDGFXR into injured arteries performed at 5 days resulted in a more than 50% reduction in the neointimal area of injured arteries at 14 days. In con- trast, the administration of control adenoviruses containing lacZ gene or containing no foreign gene was without suppressive effects on neointima formation. The inhibition of neointima formation by the expression of PDGFXR was accompanied by a reduction in bromodeoxyuridine-labeled cells and nearly complete inhibition of tyrosine phosphorylation of both α- and β-receptors for PDGF, but not of epidermal growth factor receptor, in injured arteries. This is the first report to indicate the usefulness of targeting a growth factor by expressing an extracellular binding region of a receptor using an adenovirus for the treatment of vascular proliferative disorders, and provide direct evidence that PDGF-B chain plays an essential role in neointimal formation.

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Acknowledgements

We are grateful to Dr Izumu Saito (Laboratory of Molecular Genetics, the Institute of Medical Science, University of Tokyo) for providing us with adenoviruses, Ad5dlx and AxCALacZ, and pAx1cw, and to Dr Jun-ichi Miyazaki (Department of Nutrition, Osaka University Medical School) for providing us with an expression vector, pCAGGS. We acknowledge the technical and secretarial assistance of R Suzuki, F Iwase, E Kishimoto and T Miyazawa. This work was supported by grants from the Ministry of Education, Science and Culture of Japan and the Japan Society for the Promotion of Science ‘Research for the Future’ Program, funds for cardiovascular research from Tsumura Co., and funds from Japan Heart Foundation and Japan Research Foundation for Clinical Pharmacology.

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Authors and Affiliations

  1. Department of Cardiovascular Biology, Cancer Chemotherapy Center, Cancer Institute, Tokyo, Japan

    J Deguchi, J Abe & Y Takuwa

  2. Department of Surgery, Cancer Chemotherapy Center, Cancer Institute, Tokyo, Japan

    J Deguchi, T Namba, O Sato, T Miyata & M Makuuchi

  3. Department of Molecular Biotherapy Research, Cancer Chemotherapy Center, Cancer Institute, Tokyo, Japan

    H Hamada

  4. Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan

    T Nakaoka, J Abe & K Kurokawa

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  1. J Deguchi
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Deguchi, J., Namba, T., Hamada, H. et al. Targeting endogenous platelet-derived growth factor B-chain by adenovirus-mediated gene transfer potently inhibits in vivo smooth muscle proliferation after arterial injury. Gene Ther 6, 956–965 (1999). https://doi.org/10.1038/sj.gt.3300918

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