Abstract 566: A Genetic Locus on Mouse Chromosome 11 controls Endothelial Dysfunction
Introduction: Carotid intima formation is a significant risk factor for cardiovascular disease. C3H/FeJ (C3H/F) and SJL/J (SJL) inbred mouse strains differ in susceptibility to immune and vascular traits. Using a congenic approach we demonstrated that the Intima modifier 2 (Im2) locus on chromosome 11 regulates leukocyte infiltration. We sought to determine whether inflammation was due to changes in circulating immune cells or activation of vascular wall cells in genetically pure Im2 (C3H/F.SJL.11.1) mice.
Methods and Results: Complete blood counts showed no differences in circulating cells between C3H/F and C3H/F.SJL.11.1 compared to SJL mice. Aortic vascular cell adhesion molecule-1 (VCAM-1) total protein levels were dramatically increased in SJL and C3H/F.SJL.11.1 compared to C3H/F mice. Immunostaining of aortic endothelial cells (EC) showed a significant increase in VCAM-1 expression area (um2) in SJL (0.18±0.02) and C3H/F.SJL.11.1 (0.19±0.02) compared to C3H/F (0.09±0.02) under steady flow conditions. In regions of disturbed flow we observed a significant decrease in EC area, measured by membrane staining, in SJL (500±50) and C3H/F.SJL.11.1 (500±30) versus C3H/F (800±50). Vascular permeability measured by the Miles assay (Evans’ blue dye ug per mg of aorta) was significantly higher in SJL (0.043±0.006) compared to C3H/F (0.010±0.005). In C3H/F.SJL.11.1 congenic mice vascular permeability varied from 0.006 to 0.665 but the average trended toward SJL values.
Conclusions: Our results indicate that Im2 regulation of leukocyte infiltration is mediated by EC inflammation and permeability. Comparative analysis of gene polymorphisms in human regions syntenic with the mouse Im2 locus provides new insights into candidate genes that regulate vascular wall inflammation.
Author Disclosures: E.M. Smolock: None. R.M. Burke: None. C. Wang: None. T. Thomas: None. S.N. Batchu: None. M. Zettel: None. K. Fujiwara: None. B.C. Berk: None. V.A. Korshunov: None.
This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).
- © 2014 by American Heart Association, Inc.