Smooth muscle DNA replication in response to angiotensin II is regulated differently in the neointima and media at different times after balloon injury in the rat carotid artery : Role of AT1 receptor expression

We have reported that angiotensin II (Ang II) infusion to rats during the third and fourth weeks after vascular injury stimulates DNA replication in a larger proportion of smooth muscle cells (SMCs) in the arterial neointima than in the underlying media or the normal arterial media. Whether this increased responsiveness to Ang II is a transient or stable property of neointimal cells after vascular injury remained unclear. The present study examined smooth muscle DNA replication in response to Ang II infusion (250 ng.kg-1.min-1 for 2 weeks) at 3 to 4, 9 to 10, or 27 to 28 weeks after balloon injury to the rat carotid artery. Control rats received Ringer's lactate. BrdU (0.8 mg.kg-1.d-1) was coinfused to label replicating DNA. The increased replicative response to Ang II in the neointima versus the normal arterial media did not persist beyond the period of rapid lesion growth shortly after injury, even in neointimal areas without endothelial regeneration. By 9 to 10 weeks after injury, replication frequencies were comparable in the neointima and the normal arterial wall. In the presence of a regenerated endothelium, neointimal DNA replication was lowered but not abolished. After the early period, however, the most marked difference may be the loss of ability of medial SMCs to respond mitogenically to systemic Ang II. As a consequence, Ang II-induced DNA replication in injured arteries was greater in the neointima than in the underlying media at all times studied after injury. DNA replication levels correlated with AT1 receptor levels in the injured artery neointima but not media, as shown by receptor binding in vascular sections at 3 and 10 weeks after injury. The growth response to systemic Ang II is differentially regulated in adjacent smooth muscle layers in the injured arterial wall in vivo via mechanisms that include, but are not restricted to, the regulation of AT1 receptor expression in SMCs.