¹Department of Cardiovascular Medicine, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan; Pharmaceutical Clinical Research Center, Yamaguchi University Hospital, Ube, Yamaguchi, Japan

Abstract

Background: The precise mechanisms of angiotensin II type 1 (AT1) receptors on the vascular smooth muscle cell (VSMCs) phenotype in vivo remain unclear, as studies using passaged VSMCs under conventional culture conditions have been unable to adequately investigate the molecular mechanisms underlying the phenotypic modulation of VSMCs. To clarify the mechanisms of smooth muscle (SM) cell phenotype and AT1 receptor-mediated signal transductions in hypertension, we compared the effects of an angiotensin-converting enzyme (ACE) inhibitor and AT1 receptor antagonist on vascular remodeling, oxidative stress and phenotypic changes of VSMCs.

Methods and Results: Fourteen-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were divided into 3 groups and treated for 6 weeks with either a vehicle, an ACE inhibitor (cilazapril; 10 mg/kg/day), and AT1 receptor antagonist (E4177; 30 mg/kg/day). Compared to the vehicle group, blood pressure, wall-to-lumen ratio, collagen content and the total cell number in aortic media were significantly reduced in the 2 drug-treated groups; with no significant differences between the 2 drug-treated groups. Both drugs significantly up-regulated the contractile-type SM myosin heavy chain (MHC); SM2. Whereas, they significantly down-regulated the synthetic-type SM-MHC; NMHC-B/SMemb. Total aortic reactive oxygen species (ROS) assessed by 8-iso-PGF2, the expression of NAD(P)H oxidase essential subunit, p22^phox, and p38 mitogen-activated protein kinase (p38 MAPK) were significantly reduced in the 2 drug-treated groups, and superoxide content of the aortic media assessed by hydroxyetidine staining did not differ between the 2 drug-treated groups. However, eNOS, phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt) and Cu/Zn SOD were significantly up-regulated in the 2 drug-treated groups. Additionally, E4177 induced greater increases in SM2, eNOS and p-Akt expression than did cilazapril.

Conclusions: AT1 receptor antagonists inhibited aortic VSMC phenotypic changes by the up-regulation of eNOS expression and activation of the Akt pathway, but not p38-MAPK signaling, than did ACE inhibitors in SHRSP; suggesting that AT1 receptor-mediated NO and Akt signaling might be an important determinant pathway for the aortic VSMC phenotype in hypertension in vivo.