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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:857-863.)
© 1996 American Heart Association, Inc.

Articles

Angiotensin II-Induced Progression of Neointimal Thickening in the Balloon-Injured Rat Carotid Artery Is AT₁ Receptor Mediated

Ellen M. van Kleef; Jurgen Fingerle; Mat J.A.P. Daemen

the Department of Pathology, Cardiovascular Research Institute Maastricht, University of Limburg, Maastricht, Netherlands, and the Pharma Division (J.F.), Preclinical Research, F Hoffmann-La Roche Ltd, Basel, Switzerland.

Correspondence to Mat J.A.P. Daemen, Department of Pathology, University of Limburg, PO Box 616, 6200 MD Maastricht, Netherlands. E-mail MDA@ms.azm.2.azm.nl.

To investigate the relative importance of AT₁ and AT₂ receptors in angiotensin II (Ang II)-induced restimulation of neointimal smooth muscle cell (SMC) DNA synthesis and increased neointimal cross-sectional area (CSA), male Wistar rats were subcutaneously infused for 2 weeks with Ang II and losartan, an AT₁ receptor antagonist, or Ang II and PD123319, an AT₂ receptor antagonist, during the third and fourth week after balloon injury of the left common carotid artery. Concomitantly, all rats received 5-bromo-2'-deoxyuridine to label DNA-synthesizing SMCs. Neointimal CSAs and SMC DNA synthesis were compared with control groups that received Ang II, 0.9% NaCl, losartan, or PD123319. Systolic blood pressure (SBP) was measured at different times during the infusion. Ang II induced an increase in SBP that was significantly different from the SBP in the NaCl group. Infusion of Ang II together with losartan reduced the Ang II-induced increase in SBP to levels comparable with those obtained in the NaCl group. Infusion of Ang II+PD123319 caused an increase in SBP that was comparable with the increase in SBP of the Ang II group and significantly different from the SBP of the NaCl group. Infusion of losartan or PD123319 alone did not affect SBP. Ang II significantly enhanced neointimal CSA (47%, P<.05) compared with the control group infused with NaCl. Losartan significantly reduced Ang II-induced neointimal thickening (neointimal CSA, -37%, P<.05). Infusion of PD123319 together with Ang II did not affect Ang II-induced neointimal thickening. Losartan or PD123319 alone did not reduce neointimal thickening, since the neointimal CSAs in these groups did not differ from the neointimal CSA of the NaCl group. Comparable effects were found for SMC DNA synthesis in the neointima. Ang II infusion increased neointimal SMC DNA synthesis. Addition of losartan reduced the fraction of DNA-synthesizing neointimal SMCs from 23.7±2.1% in the Ang II group to 12.8±1.8% in the Ang II+losartan group, whereas the labeling fraction in the neointima remained 26.6±3.1% in the Ang II+PD123319 group. The labeling fractions in the neointimas of the groups that received losartan or PD123319 alone did not differ from the labeling fraction in the NaCl group. These data indicate that AT₁ but not AT₂ receptors mediate the progression of neointimal thickening induced by delayed application of Ang II in the injured left carotid artery in the rat. Furthermore, these data suggest that AT₁ and AT₂ receptors are not involved in the regulation of normal growth of a neointima in the third and fourth week after balloon injury.

Key Words: restenosis • balloon injury • growth control • AT receptor antagonists

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