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Cardiovascular Research 1997 35(3):470-479; doi:10.1016/S0008-6363(97)00152-1
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

Arterial gene transfer of acidic fibroblast growth factor for therapeutic angiogenesis in vivo: critical role of secretion signal in use of naked DNA

Hirotsugu Tabata, Marcy Silver and Jeffrey M Isner*

Department of Medicine (Cardiology) and Biomedical Research, St. Elizabeth's Medical, Center of Boston, Tufts University School of Medicine, 736 Cambridge St., Boston, MA 02135, USA

* Corresponding author. Tel.: +1 617 7892392; Fax: +1 617 7895029; E-mail: jisner@opal.tufts.edu

Objective: Previous studies have demonstrated that arterial gene transfer of naked DNA encoding for a secreted protein may permit modulation of the host phenotype despite a low transfection efficiency. Acidic fibroblast growth factor (aFGF) is an angiogenic growth factor, but is not secreted by intact cells. In the current study, we investigated the hypothesis that addition of a hydrophobic leader sequence to achieve active secretion of the gene product would permit therapeutic angiogenesis following arterial gene transfer of naked DNA encoding for aFGF. Methods: Ten days following surgical induction of unilateral hindlimb ischemia, New Zealand white rabbits were randomized to intra-arterial gene transfer with one of three plasmids: p267 (encoding non-secreted aFGF, n = 10), pMJ35 (encoding secreted aFGF) (n = 10), or 500 µg of pGSVLacZ (control, n = 10) (500 µg each). All animals were studied at 30 days post-gene transfer for evidence of therapeutic angiogenesis. Results: pMJ35 transfectants had more angiographically visible collaterals (angiographic score=0.76±0.02) than either p267 (0.55±0.02, p<0.01) or LacZ (0.47±0.02, p<0.001). Limb blood pressure ratio for pMJ35 was 0.88±0.02 vs. 0.68±0.04 for p267 (p<0.01) and 0.57±0.04 for LacZ (p<0.001). Vascular resistance was significantly lower in the pMJ35 group, compared with that in pGSVLacZ group, both in resting state (3.2±0.4 vs. 7.4±1.4 respectively, p<0.05) and after the administration of nitroprusside. Capillary density (per mm2) was also superior in pMJ35 group (274±10) vs. p267 (204±9, p<0.01) and LacZ (177±6, p<0.001). Conclusion: The paracrine effects of a secreted gene product may obviate the need for adjunctive vectors in strategies of arterial gene therapy.

KEYWORDS Acidic fibroblast growth factor (aFGF); Gene therapy; Angiogenesis; Signal peptide


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