The role of the renin-angiotensin system and oxidative stress in spontaneously hypertensive rat mesenteric collateral growth impairment

Abstract

Recent clinical and animal studies have shown that collateral artery growth is impaired in the presence of vascular risk factors, including hypertension. Available evidence suggests that angiotensin-converting enzyme inhibitors (ACEI) promote collateral growth in both hypertensive humans and animals; however, the specific mechanisms are not established. This study evaluated the hypothesis that collateral growth impairment in hypertension is mediated by excess superoxide produced by NAD(P)H oxidase in response to stimulation of the ANG II type 1 receptor. After ileal artery ligation, mesenteric collateral growth did not occur in untreated, young, spontaneously hypertensive rats. Significant luminal expansion occurred in collaterals of spontaneously hypertensive rats treated with the superoxide dismutase mimetic tempol, the NAD(P)H oxidase inhibitor apocynin, and the ACEI captopril, but not ANG II type 1 (losartan) or type 2 (PD-123319) receptor blockers. The ACEI enalapril produced equivalent reduction of arterial pressure as captopril but did not promote luminal expansion. This suggests the effects of captopril on collateral growth might result from its antioxidant properties. RT-PCR demonstrated that ANG II type 1 receptor and angiotensinogen expression was reduced in collaterals of untreated rats. This local suppression of the renin angiotensin system provides a potential explanation for the lack of effect of enalapril and losartan on collateral growth. The results demonstrate the capability of antioxidant therapies, including captopril, to reverse impaired collateral artery growth and the novel finding that components of the local renin angiotensin system are naturally suppressed in collaterals.

Redox-sensitive Akt and Src regulate coronary collateral growth in metabolic syndrome

“…In agreement with our results demonstrating a beneficial effect of reduction in oxidative stress in JCR animals, Miller et al (22) demonstrated that mesenteric collateral growth, impaired in SHRs, was significantly improved by apocynin. Since a common characteristic of the JCR (29) and SHR (22) phenotype is elevated oxidative stress, these results indicate that lowering oxidative stress in phenotypes where it is elevated is critical for the restoration of collateral growth.…”

“…However, angiotensin II type 1 receptor (AT 1 R) blockade significantly restored CCG in JCR animals, which was associated with a significant reduction in myocardial O 2 Ϫ ⅐ levels (29). Decreasing ROS improved mesenteric collateral development in a rat model of spontaneous hypertension [the sponteneously hypertensive rat (SHR)] (22).…”

Impact of genetic background and aging on mesenteric collateral growth capacity in Fischer 344, Brown Norway, and Fischer 344 × Brown Norway hybrid rats

“…But we also believe that this model serves as a general model for collateral growth. In support of this are studies that show a similar impairment in collateral growth in both the hindlimb and mesentery of SHRs (10,27). In addition, we have observed similar histological results including a well-defined intima with increased endothelial cell density in vessels we have identified as primary collaterals in the hindlimbs of mice, rats, and pigs (unpublished observations).…”

Redox-Dependent Mechanisms in Coronary Collateral Growth: The “Redox Window” Hypothesis

“…Collateral growth occurs in a variety of organ systems and vascular beds, including the heart (23,114,115), hindlimb (11,12), mesentery (69), and the brain (11). In the rat heart, the response is extraordinary, with substantial increases in collateral growth in as little as 10 days (Fig.…”