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AT2R stimulation with C21 prevents arterial stiffening and endothelial dysfunction in the abdominal aorta from mice
Raquel González-Blázquez1, Martín Alcalá2, José Miguel Cárdenas-Rebollo3
1Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, 28925, Madrid, Spain.
Abstract:
The aim of the present 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). Five-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 (1 mg/kg/day, in the drinking water), generating four groups: Chow C, Chow C21, HF C, and HF C21. Vascular function and mechanical properties were determined in the abdominal aorta. To evaluate ECM remodeling, collagen deposition and TGF-β1 concentrations were determined in the abdominal aorta and the activity of metalloproteinases (MMP) 2 and 9 was 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-β1 levels in abdominal aortas together with reduced MMP activities and collagen deposition compared with HF C mice. 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.
Insights
Compound 21 (C21), an AT2R agonist, prevents obesity-induced vascular damage by preserving nitric oxide availability. This protects against endothelial dysfunction, arterial stiffness, and extracellular matrix remodeling in mice.
Area of Science:
- Cardiovascular Research
- Obesity and Metabolism
- Pharmacology
Background:
- Diet-induced obesity (DIO) is linked to endothelial dysfunction, extracellular matrix (ECM) remodeling, and arterial stiffness.
- The angiotensin II type 2 receptor (AT2R) plays a role in vascular homeostasis.
Purpose of the Study:
- To investigate the protective effects of Compound 21 (C21), a selective AT2R agonist, against vascular complications in a mouse model of DIO.
- To assess C21's impact on endothelial function, ECM remodeling, and arterial stiffness.
Main Methods:
- Male C57BL/6J mice were fed a high-fat (HF) diet or standard chow for 6 weeks.
- Mice received C21 treatment (1 mg/kg/day) or vehicle concurrently.
- Vascular function, mechanical properties, collagen deposition, TGF-β1 levels, and matrix metalloproteinase (MMP) activity were analyzed in the abdominal aorta and plasma.
Main Results:
- HF diet induced endothelial dysfunction, increased arterial stiffness (elevated β-index), and promoted ECM remodeling (collagen deposition, increased MMP activity).
- C21 treatment abrogated Ang II-induced dysfunction by preserving nitric oxide (NO) availability.
- C21 significantly reduced TGF-β1 levels, MMP activity, and collagen deposition in HF mice compared to controls.
Conclusions:
- AT2R stimulation with C21 preserves NO availability in obesity.
- C21 effectively prevents detrimental vascular remodeling, including endothelial dysfunction, ECM remodeling, and arterial stiffness in the abdominal aorta of HF mice.
