Small mesenteric arteries from UM-HET3 and C57BL/6J have similar vasodilatory mechanisms during myoendothelial feedback

Background: Myoendothelial Feedback (MEF) is an important mechanism for preventing arterial over-constriction during sympathetic vasoconstriction. Sympathetic stimulation or alpha-adrenergic stimulation of arteries causes MEF by smooth muscle to endothelial gap junction communication followed by endothelial-dependent vasodilation through nitric oxide (NO) production and endothelial-dependent hyperpolarization (EDH) mechanisms. While these mechanisms are well understood in genetically similar C57BL/6 (C57) mice arteries, the influence of genetic diversity on MEF remains poorly understood. UM-HET3 (HET3) mice are a genetically diverse, robust model commonly used in aging studies, but vascular research is lacking. Objective: The purpose of this study was to assess the influence of genetic diversity on the contributions of NO and EDH to MEF using HET3 and C57 male and female mice. Understanding these effects in mouse models may provide valuable insights into vascular regulation in genetically diverse human populations and enhance the translational relevance of preclinical studies. Hypothesis: We hypothesized that HET3 mice and C57 mice would exhibit similar contributions of eNOS and EDH to the MEF response in mesenteric resistance arteries. Methods: This study utilized 1 st and 2 nd order small mesenteric arteries from male and female C57 and HET3 mice. Arteries were isolated, cannulated, maintained under physiological conditions (75mmHg; 37°C, with no luminal flow) using pressure myography. Luminal diameter was measured (in a strain and sex-blinded manner) when arteries were superfused with phenylephrine (PE) [10 -5 M] to induce a deep constriction, followed by vasodilatory responses over 20 minutes, to determine the MEF response. MEF was calculated by % dilation at 20 min compared to peak constriction. In separate arteries, NO production was inhibited using L-NAME [10 -4 M], or EDH was blocked with 35 mM potassium chloride (KCl) in combination with L-NAME. Results: In all 4 groups (male and female HET3 and C57), L-NAME did not significantly inhibit MEF at 20 min, but L-NAME+KCl significantly inhibited MEF by more than 50% in all 4 groups[% dilation (mean ± SEM; Control vs. L-NAME+KCl) in HET3 male: 58.8 ± 4.7 (n=11) vs. 21.2 ± 4.3 (n=7) (p<0.0001), in HET3 female: 43.5 ± 2.6 (n=12) vs. 21.3 ± 4.8 (n=8) (<0.05), in C57 male: 38.8 ± 2.2 (n=15) vs. 11.0 ± 6.1 (n=8) (p<0.001), in C57 female: 47.8 ± 3.9 (n=15) vs. 9.0 ± 4.1 (n=6) (p<0.0001)], as determined by 1-way ANOVA with Bonferroni post-hoc test. Conclusion: MEF mechanisms in HET3 mouse arteries are similar to C57 and are mostly due to EDH, indicating that genetic diversity does not alter these mechanisms and validating HET3 as a useful model for this vascular function. Funded by NIH-1R15HL150570-01A1 (R.L-W.), the William & Mary Charles Center Undergraduate Summer Research Grant (E.W., K.S.), and the William & Mary FUSE program (C.H.). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.