Inbred C57BL/6J and C57BL/6N mice exhibit differential vascular dysfunction compared with outbred UM-HET3 mice

Inbred C57BL/6 mice are the most widely used laboratory mice in biomedical research. There are two C57BL/6 substrains, C57BL/6J and C57BL/6N, that are often used interchangeably incorrectly. We sought to examine vascular function in C57BL/6J and C57BL/6N mice. We observed lower systolic blood pressure and aortic stiffness in C57BL/6N versus C57BL/6J mice. Although acetylcholine-mediated vasodilation was similar between C57BL/6 substrains, flow-mediated vasodilation was greater in C57BL/6N versus C57BL/6J mice. Aortic structural characteristics were also similar between C57BL/6 substrains. These findings indicate distinct differences in vascular function between C57BL/6 substrains, indicating greater vascular function in C57BL/6N mice. To determine the effect of inbreeding on vascular function in C57BL/6J or C57BL/6N mice, we also measured vascular function in UM-HET3 mice, an outbred genetically diverse strain derived from the C57BL/6 strain. In general, UM-HET3 mice had greater vascular function than either C57BL/6 substrain, demonstrated by lower aortic stiffness, aortic medial cross-sectional area, and aortic collagen content and greater aortic elastin content, acetylcholine-mediated vasodilation, and flow-mediated vasodilation. Notably, systolic blood pressure in C57BL/6N mice was also lower than UM-HET3 mice, whereas aortic elastin content and flow-mediated vasodilation were similar between C57BL/6N and UM-HET3 mice. Importantly, greater vascular function in UM-HET3 mice was not accompanied by greater measurement variability, as coefficient of variation across all measurements was similar between strains. These findings suggest that the greater vascular function in UM-HET3 mice does not come at the expense of measurement variability, making them a viable alternative to inbred mice in biomedical research.<b>NEW & NOTEWORTHY</b> We observed major vascular physiological differences between C57BL/6J and C57BL/6N mice, indicating C57BL/6N mice have greater vascular function. However, in comparison to either C57BL/6 substrain, outbred, genetically diverse UM-HET3 mice have a greater vascular function characterized by lower aortic stiffness and greater endothelial-dependent dilation. A greater vascular function in UM-HET3 mice was not accompanied by more measurement variability, as coefficient of variation across measurements was similar between strains.