Aims: This study investigates the effect of local mechanical stimulation induced by pressure or flow-overload in right coronary artery (RCA) angiotensin II type 1 (AT1) receptor-mediated endothelial dysfunction in swine models of aortic or pulmonary artery banding.
Methods and results: A total of 36 pigs (37 ± 7 kg) were studied. The RCA was exposed to pressure-overload by aortic banding (n = 6) or blood flow-overload by pulmonary artery banding (n = 6) for 4 weeks, and sham-operated animals served as controls (n = 6). The RCA of 18 pigs were exposed to acute ex-vivo pressure-overload. The effects of local mechanical stimuli on AT1 receptor were determined by external cuff. Aortic banding caused RCA pressure-overload of 118 ± 11 mmHg in comparison with 79 ± 9 mmHg for sham controls. The cross-sectional area of the RCA lumen increased 27.9% (from 8.09 ± 0.89 to 10.3 ± 0.96 mm) when the blood flow increased by 80% (from 23.8 ± 4.3 to 44.3 ± 7.2 ml/min) in the 4-week pulmonary artery banding period. Both pressure and flow-overload resulted in the up-regulation of expression and activation of AT1 receptor. An increased production of reactive oxygen species (ROS) and endothelium dysfunction were observed in the RCA. The acute inhibition of AT1 receptor and NADPH oxidase partially restored the endothelial function. The endothelial dysfunction and activation of AT1 receptor was also realized in ex-vivo pressure-overload of normal RCA. An external cuff inhibited the increase in activation of AT1 receptor and preserved endothelial function in ex-vivo pressure-overload which implicates local wall mechanical stimulation as opposed to pressure.
Conclusion: Local mechanical stimulation activates the AT1 receptor which likely mediates ROS production and endothelial dysfunction in RCA.
aDepartment of Biomedical Engineering
bDepartment of Physics
cDepartment of Cellular and Integrative Physiology
dDepartment of Surgery
eIndiana Center for Vascular Biology and Medicine, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, USA
Correspondence to Ghassan S. Kassab, PhD, Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA. E-mail: firstname.lastname@example.org
Abbreviations: AngII, angiotensin II; ANOVA, analysis of variance; AT1, angiotensin II type 1; DAPI, 4′-6-diamidino-2-phenylindole; eNOS, endothelial nitric oxide synthesis; EPR, electron paramagnetic resonance; ERK, extracellular signal-regulated kinase; HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; MAPK, mitogen-activated protein kinase; MLCK, myosin light chain kinase; PBN, N-tert-butyl-α-phenylnitrone; PKC, protein kinase C; PSS, physiological saline solution; RCA, right coronary artery; ROS, reactive oxygen species; RVH, right-ventricular hypertrophy; VSM, vascular smooth muscle; WSS, wall shear stress
Received 17 May, 2012
Revised 19 October, 2012
Accepted 3 December, 2012