title: Intima modifier locus 2 controls endothelial cell activation and vascular permeability.
abstract: 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. Complete blood counts showed no differences in circulating monocytes between C3H/F and C3H/F.SJL.11.1 compared with 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 with C3H/F mice. Immunostaining of aortic endothelial cells (EC) showed a significant increase in VCAM-1 expression in SJL and C3H/F.SJL.11.1 compared with C3H/F under steady flow conditions. Immunostaining of EC membranes revealed a significant decrease in EC size in SJL and C3H/F.SJL.11.1 vs. C3H/F in regions of disturbed flow. Vascular permeability was significantly higher in C3H/F.SJL.11.1 compared with C3H/F. Our results indicate that Im2 regulation of leukocyte infiltration is mediated by EC inflammation and permeability. RNA sequencing and pathway analyses comparing genes in the Im2 locus to C3H/F provide insight into candidate genes that regulate vascular wall inflammation and permeability highlighting important genetic mechanisms that control vascular intima in response to injury.
authors.affiliation: Department of Medicine and Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Smolock
authors.affiliation: Department of Medicine and Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Burke
authors.affiliation: Department of Medicine and Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York; Function Teaching and Research Section, Medical College of Northwest University for Nationalities, Lanzhou, China.
authors.forename: Chenjing
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Medicine and Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: Tamlyn
authors.initials: T
authors.lastname: Thomas
authors.affiliation: Department of Medicine and Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: Sri N
authors.initials: SN
authors.lastname: Batchu
authors.affiliation: Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York; and.
authors.forename: Xing
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Medicine and Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: Martha
authors.initials: M
authors.lastname: Zettel
authors.affiliation: Department of Medicine and Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: Keigi
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: Department of Medicine and Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York;
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
authors.affiliation: Department of Medicine and Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York; Slava_Korshunov@urmc.rochester.edu.
authors.forename: Vyacheslav A
authors.initials: VA
authors.lastname: Korshunov
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D048429:Cell Size; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D004730:Endothelium, Vascular / Q000473:pathology* / Q000503:physiopathology*; D063990:Gene Ontology; D056426:Genetic Loci; D016678:Genome / Q000235:genetics; D007249:Inflammation / Q000473:pathology; D008297:Male; D020297:Mice, Congenic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017423:Sequence Analysis, RNA; D017539:Tunica Intima / Q000473:pathology* / Q000503:physiopathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D019010:Vascular Cell Adhesion Molecule-1
keywords: C3Heb/Fe; SJL; congenics; endothelial cell; inflammation; permeability