Local Application of Angiotensin II to the Rat Carotid Artery Induces Adventitial Thickening

The aim of this study was to determine the effects of angiotensin II (Ang II) on the vascular wall, that are independent of its effects on systemic blood pressure. Ang II has been shown to have different effects on vascular growth in vitro and in vivo. The generally weak effects of Ang II in cell culture may be due to the absence of blood-borne factors and interactions between different cell types, dedifferentiation of cells and receptor loss. On the other hand, studies with administration of Ang II in vivo are complicated by effects on blood pressure and it is not clear whether the effects of Ang II are direct or secondary. In order to overcome some of these limitations, we delivered Ang II locally to the left carotid artery of normotensive rats with a perivascular drug delivery system, in doses that did not affect systemic blood pressure. Ang II was applied perivascularly to the artery in doses of 0.05, 0.5, 5 and 50 ng/h for 14 days. A vehicle-treated group and the right carotid artery served as controls. Other groups received noradrenaline as a control for the vasoconstrictive actions of Ang II. Ang II, but not noradrenaline, induced a dose-dependent thickening of the adventitia with increased cellularity which was characterized by DNA synthesis, neovascularization, and collagen deposition. Administration of specific ligands for the AT1 and AT2 receptors in the presence or absence of Ang II indicates that the increased cellularity and collagen deposition are mediated via the AT1 receptor, are inhibited via stimulation of the AT2 receptor, and that the angiogenesis may be mediated via the AT2 receptor. In conclusion, Ang II, independent of its effect on systemic blood pressure, induces a specific and receptor-dependent adventitial growth response when delivered perivascularly to the carotid artery.