Endothelium-dependent relaxation is impaired in Schlager hypertensive (BPH/2J) mice by region-specific mechanisms in conductance and resistance arteries

• Published in: Life sciences (1973) 2023-05, Vol.320, p.121542-121542, Article 121542
• Main Authors: Jelinic, Maria, Jackson, Kristy L., O'Sullivan, Kelly, Singh, Jaideep, Giddy, Thomas, Deo, Minh, Parry, Laura J., Ritchie, Rebecca H., Woodman, Owen L., Head, Geoffrey A., Leo, Chen Huei, Qin, Cheng Xue
• Format: Article
• Language: English
• Subjects: Animals; Arteries - pathology; Blood Pressure - physiology; Endothelial dysfunction; Endothelium - pathology; Endothelium, Vascular - pathology; Humans; Hypertension; Male; Mesenteric Arteries; Mice; Nitric oxide; Passive mechanics; Prostanoids; Prostatic Hyperplasia; Sympathetic Nervous System - physiology; Vascular compliance; Vasodilation
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2023.121542

Endothelial dysfunction and arterial stiffness are hallmarks of hypertension, and major risk factors for cardiovascular disease. BPH/2J (Schlager) mice are a genetic model of spontaneous hypertension, but little is known about the vascular pathophysiology of these mice and the region-specific differences between vascular beds. Therefore, this study compared the vascular function and structure of large conductance (aorta and femoral) and resistance (mesenteric) arteries of BPH/2J mice with their normotensive BPN/2J counterparts. Blood pressure was measured in BPH/2J and BPN/3J mice via pre-implanted radiotelemetry probes. At endpoint, vascular function and passive mechanical wall properties were assessed using wire and pressure myography, qPCR and histology. Mean arterial blood pressure was elevated in BPH/2J mice compared to BPN/3J controls. Endothelium-dependent relaxation to acetylcholine was attenuated in both the aorta and mesenteric arteries of BPH/2J mice, but through different mechanisms. In the aorta, hypertension reduced the contribution of prostanoids. Conversely, in the mesenteric arteries, hypertension reduced the contribution of both nitric oxide and endothelium-dependent hyperpolarization. Hypertension reduced volume compliance in both femoral and mesenteric arteries, but hypertrophic inward remodelling was only observed in the mesenteric arteries of BPH/2J mice. This is the first comprehensive investigation of vascular function and structural remodelling in BPH/2J mice. Overall, hypertensive BPH/2J mice exhibited endothelial dysfunction and adverse vascular remodelling in the macro- and microvasculature, underpinned by distinct region-specific mechanisms. This highlights BPH/2J mice as a highly suitable model for evaluating novel therapeutics to treat hypertension-associated vascular dysfunction. Schlager (BPH/2J) mice are a robust model of hypertensive vascular disease. The aorta, femoral and mesenteric arteries of hypertensive BPH/2J mice were compared to those of normotensive BPN/3J controls. In the aorta, hypertension reduced endothelium-dependent relaxation (reduced contribution of prostanoids (PGs)) and increased contraction to phenylephrine (PE; with reduced α1-adrenoreceptor (Adra1a) and increased α2-adrenoreceptor (Adra2a) gene expression). In femoral arteries, hypertension reduced volume compliance and elastin content without geometric remodelling. In mesenteric arteries, hypertension reduced endothelium-dependent relaxation (reduc