Abstract 15931: Murine Strain-Related Genetic Modifier of Endothelial Function Maps to Novel Locus
Background: Endothelial dysfunction precedes the development of atherosclerosis. While dietary factors, hypertension, and smoking are associated with endothelial dysfunction, genetic determinants of endothelial dysfunction are not well established. To investigate potential mouse strain effects on endothelial function, we generated congenic lines of mice carrying genetic contributions from the C57BL/6J and KKhij strains and then measured endothelial function.
Methods: KK/HIJ mice were crossed to a pure C57BL/6J strain for 3-4 generations. To assess vascular function in these mice, mesenteric arterioles were mounted on a pressure myograph system and norepinephrine (NE)-induced vasoconstriction, acetylcholine (Ach)-induced endothelium-dependent, and sodium nitroprusside (SNP)-induced endothelium-independent vasorelaxation were evaluated. Based on the functional studies, a genome-wide scan (density of 10-20 Mbs) was conducted using single nucleotide polymorphisms (SNPs) to determine strain identity at each locus.
Results: Vasoconstriction responses to NE were similar among these mixed strain mice, however endothelium-dependent vasorelaxation responses to Ach were highly variable in these mice with half of the offspring showing maximal relaxation from 70% - 98%, similar to pure C57BL/6J mice, while others showed impaired responses with maximal relaxation from 10%-30%. Endothelium-independent responses to SNP were similar in all these mice. Genome-wide scanning revealed 85% of all loci were homozygous for C57BL/6J markers while 15% were heterozygous for KKhij markers. Mice with impaired endothelial function were heterozygous for KKhij alleles in a 10 Mb region while mice with normal endothelial function were homozygous for C57BL/6J alleles at this region.
Conclusions: A heterozygous murine strain modifier of endothelial function is present in a novel chromosomal region. Additional fine mapping may reveal a novel, potent genetic regulator of endothelial function.
- © 2011 by American Heart Association, Inc.