AT2R stimulation with C21 prevents arterial stiffening and endothelial dysfunction in the abdominal aorta from mice fed a high-fat diet

Abstract

The aim of this study was to evaluate the effect of Compound 21 (C21), a selective AT2R agonist, on the prevention of endothelial dysfunction, extracellular matrix (ECM) remodeling and arterial stiffness associated with diet-induced obesity (DIO).  5-week-old male C57BL/6J mice were fed a standard (Chow) or high-fat diet (HF) for 6 weeks. Half of the animals of each group were simultaneously treated with C21 (1mg/kg/day, in the drinking water), generating 4 groups: Chow C, Chow C21, HF C, HF C21. Vascular function and mechanical properties were determined in the abdominal aorta. To evaluate ECM remodeling, collagen deposition, activity of metalloproteinases (MMP) 2 and 9 and TGF-b1 concentration were analyzed in the plasma. Abdominal aortas from HF C mice showed endothelial dysfunction as well as enhanced contractile but reduced relaxant responses to Ang II. This effect was abrogated with C21 treatment by preserving NO availability. A left-shift in the tension-stretch relationship, paralleled by an augmented β-index (marker of intrinsic arterial stiffness), and enhanced collagen deposition and MMP-2/-9 activities were also detected in HF mice. However, when treated with C21, HF mice exhibited lower TGF-b1 levels in abdominal aortas together with reduced MMP activities and collagen deposition compared with HF C mice.</p>  In conclusion, these data demonstrate that AT2R stimulation by C21 in obesity preserves NO availability and prevents unhealthy vascular remodeling, thus protecting the abdominal aorta in HF mice against the development of endothelial dysfunction, ECM remodeling and arterial stiffness.

Short‐term dietary intervention improves endothelial dysfunction induced by high‐fat feeding in mice through upregulation of the AMPK‐CREB signaling pathway

“…It is important to note that studies of our group have previously revealed vascular alterations, including endothelial dysfunction and a defective NO release, in mice fed a HF diet for 6 weeks. [17][18][19] The main findings of this study are that restoring a healthy diet for a period as short as 2 weeks after HF diet intake was enough to reduce BW and improve metabolic parameters, endothelial function, and AMPKderived vascular responses in the thoracic aorta, due to the activation of the AMPK/CREB signaling pathway.…”

“…Hypercaloric diets, including not only HF 7,[16][17][18][19] but also high sucrose 20,21 and high fructose 22,23 diets, have all been shown to induce metabolic and vascular alterations. Several strategies, including moderate CR 24,25 and more recently, IF 26,27 or even time-restricted eating 28 have emerged as effective interventions for BW loss and improved health outcomes.…”

Arterial Stiffness Assessment by Pulse Wave Velocity in Patients with Metabolic Syndrome and Its Components: Is It a Useful Tool in Clinical Practice?

“…In addition, brachial–ankle PWV values after weight regaining were independent of body weight, high-sensitivity C-reactive protein (hs-CRP), or insulin resistance changes [ 56 ]. However, it is still unknown what impacts a decrease in PWV value after weight reduction the most; whether it depends on changes in adipokines and inflammatory markers or is due to weight reduction per se [ 57 , 58 ].…”

Angiotensin II type 2 receptor as a novel activator of brown adipose tissue in obesity

“…In our model, C21‐mediated activation of iBAT in HFD‐fed mice did not modify body mass, but successfully reduced circulating insulin levels. In addition, previous reports from our group in these animals showed that C21 preserves the endothelial function in thoracic and abdominal aorta from obese mice, 26,27 demonstrating a role in cardiovascular protection. According to our results, C21 enhances BAT activity in obese mice by (i) enhancing thermogenesis via ETC and UCP1 upregulation; (ii) increasing BAT mass through a promotion of cell differentiation, and (iii) improving BAT function through a reduction in inflammation and oxidative stress.…”

“…The vascular effects of this experimental approach have been previously reported in Gonz alez-Bl azquez et al 26,27 The experimental procedures were performed in accordance with the European Union Laboratory Animal Care Rules (86/609/ECC directive) and approved by the Ethical Committee of the San Pablo CEU University and the Animal Protection Area of the Comunidad Aut onoma de Madrid (PROEX 200/18).…”