title: Congenic fine-mapping identifies a major causal locus for variation in the native collateral circulation and ischemic injury in brain and lower extremity.
abstract: BACKGROUND
  Severity of tissue injury in occlusive disease is dependent on the extent (number and diameter) of collateral vessels, which varies widely among healthy mice and humans. However, the causative genetic elements are unknown. Recently, much of the variation among different mouse strains, including C57Bl/6J (B6, high extent) and BALB/cByJ (Bc, low extent), was linked to a quantitative trait locus on chromosome 7 (Candq1).
  
  
  OBJECTIVE
  We used congenic mapping to refine Candq1 and its candidate genes to create an isogenic strain set with large differences in collateral extent to assess their impact and the impact of Candq1, alone, on ischemic injury.
  
  
  RESULTS
  Six congenic strains possessing portions of Candq1 introgressed from B6 into Bc were generated and phenotyped. Candq1 was refined from 27 to 0.737 Mb with full retention of effect, that is, return or rescue of phenotypes from the poor values in Bc to nearly those of wild-type B6 in the B6/B6 congenic mice as follows: 83% rescue of low pial collateral extent and 4.5-fold increase in blood flow and 85% reduction of infarct volume after middle cerebral artery occlusion; 54% rescue of low skeletal muscle collaterals and augmented recovery of perfusion (83%) and function after femoral artery ligation. Gene deletion and in silico analysis further delineated the candidate genes.
  
  
  CONCLUSIONS
  We have significantly refined Candq1 (now designated determinant of collateral extent 1; Dce1), demonstrated that genetic background-dependent variation in collaterals is a major factor underlying differences in ischemic tissue injury, and generated a congenic strain set with wide allele dose-dependent variation in collateral extent for use in investigations of the collateral circulation.
authors.affiliation: From the Departments of Cell Biology and Physiology (R.S., H.Z., J.L.L., J.E.F.) and Surgery (S.M.M.), and The McAllister Heart Institute (H.Z., J.L.L., J.E.F.), School of Medicine, University of North Carolina at Chapel Hill, NC.
authors.forename: Robert
authors.initials: R
authors.lastname: Sealock
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Lucitti
authors.forename: Scott M
authors.initials: SM
authors.lastname: Moore
authors.forename: James E
authors.initials: JE
authors.lastname: Faber
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply*; D002874:Chromosome Mapping / Q000379:methods*; D003097:Collateral Circulation / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D023281:Genomics / Q000379:methods; D006239:Haplotypes; D006579:Heterozygote; D006614:Hindlimb / Q000098:blood supply*; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics* / Q000503:physiopathology; D007511:Ischemia / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D040641:Quantitative Trait Loci
keywords: collateral circulation; genetics; models, animal; peripheral vascular diseases