Blood Pressure, Artery Size, and Artery Compliance Parallel Bone Size and Strength in Mice With Differing Ece1 Expression

Abstract

The recombinant congenic mouse strains HcB8 and HcB23 differ in femoral shape, size, and strength, with HcB8 femora being more gracile, more cylindrical, weaker, and having higher Young's modulus. In previous work, we mapped a robust, pleiotropic quantitative trait locus for these bone traits. Ece1, encoding endothelin converting enzyme 1, is a positional candidate gene for this locus, and was less expressed in HcB8 bone. We hypothesized that the same genetic factors would impose analogous developmental trajectories on arteries to those in bones. Cardiovascular hemodynamics and biomechanics of carotids were measured in adult HcB8 and HcB23 mice. Biological differences in heart and arteries were examined at mRNA and protein levels. As in bone, Ece1 expression was higher in HcB23 heart and arteries (p < 0.05), and its expression was correlated with that of the endothelin B type receptor target Nos3, encoding endothelial nitric oxide synthase. HcB8 mice had higher ambulatory blood pressure (p < 0.005) than HcB23 mice. Ex vivo, at identical pressures, HcB8 carotid arteries had smaller diameters and lower compliance (p < 0.05), but the same elastic modulus compared to HcB23 carotid arteries. HcB8 hearts were heavier than HcB23 hearts (p < 0.01). HcB8 has both small, stiff bones and small, stiff arteries, lower expression of Ece1 and Nos3, associated in each case with less favorable function. These findings suggest that endothelin signaling could serve as a nexus for the convergence of skeletal and vascular modeling, providing a potential mechanism for the epidemiologic association between skeletal fragility and atherosclerosis.