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Effects of local gene transfer of VEGF on neointima formation after balloon injury in hypercholesterolemic rabbits

Clinical Division of Cardiology, Innsbruck Medical University, Austria, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland

Severin P Schwarzacher

Clinical Division of Cardiology, Innsbruck Medical University, Austria

Ralf H Zwick

Clinical Division of Cardiology, Innsbruck Medical University, Austria

Hannes Alber

Clinical Division of Cardiology, Innsbruck Medical University, Austria

Gunda Millonig

Department of General and Experimental Pathology, Innsbruck University, Austria

Caecilia Weiss

Clinical Division of Cardiology, Innsbruck Medical University, Austria

Heike Hügel

Clinical Division of Cardiology, Innsbruck Medical University, Austria

Matthias Frick

Clinical Division of Cardiology, Innsbruck Medical University, Austria

Alicja Jozkowicz

Faculty of Biotechnology, Jagiellonian University, Krakow, Poland

Otmar Pachinger

Clinical Division of Cardiology, Innsbruck Medical University, Austria

Franz Weidinger

Clinical Division of Cardiology, Innsbruck Medical University, Austria, f.weidinger{at}uibk.ac.at

Enhancement of the generation of nitric oxide (NO) and vascular endothelial growth factor (VEGF) are suggested to prevent restenosis after angioplasty. Accordingly, we tested whether the local delivery of L-arginine (L-Arg), a substrate for NO generation and the VEGF gene, alone or in combination, can influence neointima formation in hypercholesterolemic rabbits. Balloon injury of the iliac arteries was performed in 24 New Zealand White rabbits fed a 1% cholesterol diet for 3 weeks followed by a local infusion of: (1) pSG5VEGF₁₆₅ plasmid alone (1000 µg); (2) pSG5VEGF₁₆₅ (1000 µg) with L-Arg (800 mg); (3) L-Arg (800 mg) alone; and (4) L-Arg (800 mg) with naked pSVß-gal plasmid (1000 µg). The animals were kept on the hypercholesterolemic diets for a further 28 days, when vessels were taken for morphometric analysis and immunocytochemistry. Endogenous rabbit VEGF concentration in the plasma increased significantly at 7 days after injury (17.06 ± 1.57 vs 23.01 ± 1.9 pg/ml; p < 0.02) and remained elevated for up to 28 days (28.46 ± 5.24; p < 0.01). Injured arteries exhibited strong immunocytochemical staining for rabbit VEGF. Rabbits that received a VEGF gene transfer revealed more prominent neointima formation, whereas treatment with L-Arg was associated with significantly less intimal thickness (p < 0.05). Local transfer of the VEGF gene does not inhibit neointima formation in hypercholesterolemic rabbits. Our results suggest that VEGF gene therapy applied locally in atherosclerotic arteries may not be beneficial.

Key Words: atherosclerosis • gene therapy • vascular endothelial growth factor

Vascular Medicine, Vol. 10, No. 4, 285-291 (2005)
DOI: 10.1191/1358863x05vm630oa


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