Wang Zhijie, Kristianto Jasmin, Yen Ooi Chen, Johnson Michael G, Litscher Suzanne J, Pugh Thomas D, Sandhu Gurpreet, Chesler Naomi C, Blank Robert D
Department of Biomedical Engineering, University of Wisconsin, 2146 ECB, 1550 Engineering Drive, Madison, WI 53706, USA.
J Biomech Eng. 2013 Jun;135(6):61003-9. doi: 10.1115/1.4024161.
The recombinant congenic mouse strains HcB-8 and HcB-23 differ in femoral shape, size, and strength, with HcB-8 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 HcB-8 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 HcB-8 and HcB-23 mice. Biological differences in heart and arteries were examined at mRNA and protein levels. As in bone, Ece1 expression was higher in HcB-23 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. HcB-8 mice had higher ambulatory blood pressure (p < 0.005) than HcB-23 mice. Ex vivo, at identical pressures, HcB-8 carotid arteries had smaller diameters and lower compliance (p < 0.05), but the same elastic modulus compared to HcB-23 carotid arteries. HcB-8 hearts were heavier than HcB-23 hearts (p < 0.01). HcB-8 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.
重组近交系小鼠品系HcB - 8和HcB - 23在股骨形状、大小和强度方面存在差异，HcB - 8的股骨更纤细、更呈圆柱形、更脆弱且杨氏模量更高。在之前的研究中，我们为这些骨骼性状定位了一个强大的多效性数量性状基因座。编码内皮素转换酶1的Ece1是该基因座的一个位置候选基因，在HcB - 8骨骼中的表达较低。我们推测相同的遗传因素会对动脉施加与骨骼中类似的发育轨迹。在成年HcB - 8和HcB - 23小鼠中测量了颈动脉的心血管血流动力学和生物力学。在mRNA和蛋白质水平检测了心脏和动脉的生物学差异。与骨骼一样，Ece1在HcB - 23心脏和动脉中的表达更高（p < 0.05），其表达与内皮素B型受体靶点Nos3（编码内皮型一氧化氮合酶）的表达相关。HcB - 8小鼠的动态血压高于HcB - 23小鼠（p < 0.005）。在体外，在相同压力下，HcB - 8颈动脉的直径较小且顺应性较低（p < 0.05），但与HcB - 23颈动脉的弹性模量相同。HcB - 8心脏比HcB - 23心脏更重（p < 0.01）。HcB - 8既有小而硬的骨骼，又有小而硬的动脉，Ece1和Nos3的表达较低，在每种情况下都与不太有利的功能相关。这些发现表明内皮素信号传导可能是骨骼和血管建模汇聚的枢纽，为骨骼脆性与动脉粥样硬化之间的流行病学关联提供了一种潜在机制。
