Vasomotor Dysfunction Early after Exposure of Normal Rabbit Arteries to an Adenoviral Vector

Abstract

We aimed to investigate whether infection of normal rabbit arteries with a recombinant adenovirus vector would result per se in alterations in contractile and endothelial functions. In one group of rabbits, right or left femoral and ear artery segments were injected in vivo with a replication-deficient adenoviral vector expressing a β-galactosidase (β-Gal) reporter gene (4 × 10¹⁰ pfu/ml) to demonstrate efficient gene transfer. Contralateral arteries were injected with the same concentration of a recombinant adenoviral vector carrying no transgene (Ad.MLPnull). In another group of animals, Ad.MLPnull was injected into the lumen of femoral and ear artery segments. The contralateral arteries were used as controls with the injection of vehicle alone. Histochemical assessment of gene transfer using β-Gal activity (group 1) or in vitro contractility and endothelial function (group 2) was performed 3 days after adenoviral infection. Gene transfer was efficient and reproducible in the endothelium and was associated with the presence of inflammatory cells in the media. In Ad.MLPnull-injected arteries, in vitro contractile response of femoral artery rings to either KC1 60 mM or phenylephrine (10 μM) was reduced to 10.5 ± 2.3% (n = 14;p < 0.001) and 8.8 ± 2.0% (n = 7;p < 0.001) of the control values, respectively. Furthermore, in arteries injected with Ad.MLPnull, the endothelium-dependent relaxation produced by acetylcholine (10 μM) was virtually abolished. Similarly, the relaxant effects of the α ₂-adrenoreceptor agonist UK14304 (1 μM) or the Ca²⁺ ionophore A23187 (1 μM) were also abolished. By contrast, sodium nitroprusside (10 μM) was still able to relax adenovirus-infected arteries. We conclude that infection with a recombinant adenoviral vector can induce early severe vasomotor alterations in both contractile function and endothelium-mediated relaxation of normal rabbit arteries.

Overview summary

The goal of this study was to evaluate the effects of adenoviral gene transfer on arterial vasomotricity. Replication-deficient first-generation adenoviral vectors were injected in vivo into rabbit ear and femoral arteries. Efficient gene transfer was evaluated using the LacZ reported gene. Arteries injected with an adenoviral vector exhibited in vitro altered contractility and impaired response to vasorelaxant agents. It is concluded that intravascular infection with a first-generation adenoviral vector can induce severe vasomotor alterations.