title: Blood pressure, artery size, and artery compliance parallel bone size and strength in mice with differing ece1 expression.
abstract: 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 &lt; 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 &lt; 0.005) than HcB-23 mice. Ex vivo, at identical pressures, HcB-8 carotid arteries had smaller diameters and lower compliance (p &lt; 0.05), but the same elastic modulus compared to HcB-23 carotid arteries. HcB-8 hearts were heavier than HcB-23 hearts (p &lt; 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.
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin, 2146 ECB, 1550 Engineering Drive, Madison, WI 53706, USA.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Wang
authors.forename: Jasmin
authors.initials: J
authors.lastname: Kristianto
authors.forename: Chen
authors.initials: C
authors.lastname: Yen Ooi
authors.forename: Michael G
authors.initials: MG
authors.lastname: Johnson
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Litscher
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Pugh
authors.forename: Gurpreet
authors.initials: G
authors.lastname: Sandhu
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Chesler
authors.forename: Robert D
authors.initials: RD
authors.lastname: Blank
mesh_terms: D000818:Animals; D001158:Arteries / Q000033:anatomy & histology* / Q000502:physiology*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001696:Biomechanical Phenomena; D001794:Blood Pressure; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000502:physiology*; D003187:Compliance; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000378:metabolism; D005786:Gene Expression Regulation; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity
chemical_list: D016232:Endothelins; D012333:RNA, Messenger; D009569:Nitric Oxide; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes