Abstract
Objective: Genetically diverse UM-HET3 (HET3) mice have emerged as a more robust model of human large artery dysfunction than the commonly used inbred C57BL/6J (C57) mice. However, HET3 resistance artery function has not been examined. The purpose of this study was to examine HET3 versus C57 mesenteric resistance artery agonist-induced vasomotor responses to phenylephrine (PE) and acetylcholine (ACh), PE-induced myoendothelial feedback (endothelium-dependent feedback dilation to PE-induced vasoconstriction) and its underlying mechanisms, and eNOS (an enzyme involved in endothelium-dependent dilation) expression. Hypothesis: Vasomotor responses, mechanisms, and eNOS protein expression would be similar between HET3 and C57 mesenteric resistance arteries of both sexes. Methods: First- and second-order mesenteric arteries from male and female (8-18 weeks old) HET3 and C57 mice were isolated and cannulated for pressure myography. The luminal diameter was measured (in a group-blinded manner) during cumulative addition of PE [10-9-10-5 M] and then ACh [10-10-10-4 M]. In separate arteries, myoendothelial feedback was measured by diameter responses (constriction followed by endothelium-dependent feedback dilation) to 10-5 M PE over 20 min, ± nitric oxide synthase (NOS) inhibition (10-5 M L-NAME) and ± hyperpolarization inhibition with 35 mM KCl to assess myoendothelial feedback mechanisms. eNOS protein expression was measured by Western blot. Results: Arteries from all groups were similar in size (group mean range: 213-218 µm) and exhibited negligible basal tone (group mean range: 1%-4% constriction). PE-induced peak vasoconstriction (range: 71.0%-73.8% constriction; n = 11-12) and EC-50's (range: 1.03-1.54 µM) were similar between groups. ACh-induced peak vasodilation (range: 63.1%-73.4% dilation) was also similar between groups. However, ACh EC-50 was significantly (p < 0.05; ANOVA, Bonferroni) lower in HET3 female (0.047 ± 0.021 µM) than in C57 female arteries (4.22 ± 1.97 µM) (p < 0.05). Myoendothelial feedback responses were similar between groups (group mean range: 23.3%-34.0% dilation) at 10 min, but responses were significantly (p < 0.01) greater in HET3 males (56.5% ± 4.9%) than in C57 male arteries (38.8% ± 2.2%) at 20 min (n = 12-15), and they were predominantly dependent on hyperpolarization mechanisms. eNOS/GAPDH and eNOS/total protein expression were similar between the groups. Significance: In this study, HET3 mesenteric resistance arteries were found to exhibit vasomotor responses similar to those of C57 arteries, with some indications of greater endothelium-dependent vasodilation in HET3, making it a viable mouse model for vascular studies.