Restoring Blood Pressure in Hypertensive Mice Fails to Fully Reverse Vascular Stiffness

Abstract

Background: Hypertension is a well-established driver of vascular remodeling and stiffening. The goal of this study was to evaluate whether restoring normal blood pressure (BP) fully restores vascular stiffness toward that of normotensive controls. Methods: C57Bl6/J male mice received angiotensin II (angII; 1 µg/kg/min) via infusion pump for 8 weeks (hypertension group: HH), angII for 4 weeks (hypertension group: H4), angII for 4 weeks followed by 4 weeks of recovery (reversal group: HN), or sham treatment (normotensive group: NN). BP, heart rate, and pulse wave velocity (PWV) were measured longitudinally. At the end of the study period, aortas were harvested for testing of vasoreactivity, passive mechanical properties, and vessel structure. Results: The HH group exhibited a sustained increase in BP and PWV over the 8week period (p < 0.01). In the HN group, BP and PWV increased during the 4-week angII infusion, and, though BP was restored during the 4-week recovery, PWV exhibited only partial restoration (p < 0.05). Heart rate was similar in all cohorts. Compared to NN controls, both HH and HN groups had significantly increased wall thickness (p < 0.05 HH vs. NN, p < 0.01 HN vs. NN), mucosal extracellular matrix accumulation (p < 0.0001 HH vs. NN, p < 0.05 HN vs. NN), and intralamellar distance (p < 0.001 HH vs. NN, p < 0.01 HN vs. NN). Both intact and decellularized vessels were noted to have significantly higher passive stiffness in the HH and H4 cohorts than in NN controls (p < 0.0001). However, in the HN cohort, intact vessels were only modestly stiffer than those of NN controls, and decellularized HN vessels were identical to those from the NN controls. Compared to NN controls, the HH and HN cohorts exhibited significantly diminished phenylephrine-induced contraction (p < 0.0001) and endothelium-dependent vasodilation (p < 0.05). Conclusion: Hypertension causes a significant increase in in vivo aortic stiffness that is only partially reversible after BP normalization. Although hypertension does lead

Identification of Aortic Proteins Involved in Arterial Stiffness in Spontaneously Hypertensive Rats Treated With Perindopril:A Proteomic Approach

“…While there are several classes of therapeutic agents to control pressure ( Chobanian, 2017 ; Cuspidi et al, 2018 ; Unger et al, 2020 ), ACE inhibitors are highly recommended because of their cardio- and vascular protective effects ( Ferrari et al, 2005 ; Janic et al, 2014 ; Chobanian, 2017 ). This study confirmed the participation of RAS in hypertension, as shown elsewhere ( Marque et al, 2002 ; Safar, 2010 ; Hong et al, 2013 ; Natalin et al, 2016 ; Mancini et al, 2017 ; Steppan et al, 2020 ), since 8 weeks of perindopril treatment significantly reduced BP (−11%), as shown by the time course of SBP. We did not measure PWV at the beginning of the treatment, but since we have shown that PWV positively correlates with BP in SHR ( Fabricio et al, 2020 ), we may assume that PWV was also high at the beginning of the protocol.…”

“…Even though it is not clear whether arterial stiffness precedes hypertension or it is a consequence ( Kaess et al, 2012 ; Mitchell, 2014 ; Celik et al, 2017 ; Rode et al, 2020 ), several studies have shown a significant correlation between PWV and BP ( Laurent et al, 2009 ; Phillips et al, 2015 ; Steppan et al, 2020 ), including the present study, and the growing incidence of cardiovascular events in patients with high PWV values is eminent ( Niiranen et al, 2017 ; Nilsson Wadstrom et al, 2019 ; Scuteri et al, 2020 ). Therefore, it is important to determine the mechanisms involved in vascular stiffening.…”

“…In agreement, Mahmud and Feely (2002) have shown that PWV reduces independent of BP in hypertensive humans treated with Valsartan (AT1 antagonist) and captopril (ACEi). Recently, Steppan et al (2020) showed that the restoration of normal BP in hypertensive mice (recovery period after stopping Ang II infusion) results in a partial recovery of overall in vivo stiffness (PWV). These authors suggest that restoration of BP improves the viscoelastic nature of blood vessels and partially recover the matrix mechanics, but the stiffness, which is irreversible, results from endothelial dysfunction and molecular changes to the vascular matrix, which contribute to VSMC dysregulation and are the major contributor to the overall in vivo vascular stiffness in essential hypertension.…”

“…In addition, Ang II is a powerful mitogen that causes structural alterations in the vessel wall by stimulating the hypertrophy and hyperplasia of VSMCs, causing increases in the intralamellar distance on the vessel wall, increase of collagen, reduction of the elastin, and stiffness of intact and decellularized segments, among others ( Wagenseil and Mecham, 2012 ; Mancini et al, 2017 ; Steppan et al, 2020 ). However, how exactly Ang II may modulate PWV is not completely known.…”

“…Aortic stiffening is associated with either a remodeling or disorganization of the vascular wall, which derives from an increased collagenous material, fibrotic components, the presence of elastin fiber fracture, arterial elasticity, or vascular smooth muscle cell (VSMC) hypertrophy ( Morgan et al, 2014 ; Lindesay et al, 2016 , 2018 ; Fabricio et al, 2020 ; Steppan et al, 2020 ). Among several causes of aortic stiffness, the central role of the renin–angiotensin system (RAS) is well known, and therefore, some studies have shown the effects of RAS inhibition on arterial stiffness ( Marque et al, 2002 ; Gonzalez et al, 2018 ) and, consequently, on BP, but the exact molecular mechanisms induced by RAS on aortic stiffness are not completely understood.…”