Angiotensin AT2 receptor agonist, compound 21, maintains vascular integrity and prevents abdominal aortic aneurysm progression in the rat

Abstract

The effects of the selective angiotensin AT2 receptor agonist, compound 21 (C21), on abdominal aortic aneurysm (AAA) formation were investigated in normotensive Wistar rats.AAA was induced by perfusion of isolated aortic segments with elastase (Anidjar/Dobrin model). Treatment with C21 (0.03 and 0.3 mg/kg daily) was started after surgery and continued for 14 days. Sham operated animals and vehicle-treated animals after aneurysm induction (AI) served as controls. Aortic diameter and wall properties (distensibility, pulse propagation velocity) were measured infrarenally via ultrasound. Hemodynamic parameters, aortic tissue protein expression and serum cytokines were analysed.On day 14 post AI, aortic diameter of vehicle-treated animals was increased 1,6-fold compared to sham operated rats (p < 0.0001). C21 (0.03 mg/kg) decreased aortic diameter in comparison to vehicle (1.9mm ± 0.06 vs. 2.65mm ± 0.06; p < 0.0001). Infrarenal blood velocity and aortic distensibility were reduced, whereas aortic wall stiffness was increased post AI. These alterations were significantly ameliorated by treatment with C21 (p < 0.0001; p < 0.0001; p < 0.05). Blood pressure and cardiac contractility were not altered. Protein expression of IL1 beta, NF kappa B, MMP9, TGF-beta1 and MLKL in the aorta was significantly (p < 0.05) down-regulated in the C21 group compared with vehicle. In primary rat vascular smooth muscle cells, the release of MMP9, TGF-beta1 and MLKL was significantly diminished after C21 (1mM) treatment. Serum concentration of TGF-beta1 was also decreased by C21 in comparison to vehicle (p < 0.01).In conclusion, AT2 receptor stimulation with C21 prevented extracellular matrix degradation, maintained vascular integrity of the aorta and prevented AAA progression.