Genetic architecture underlying variation in extent and remodeling of the collateral circulation.
BACKGROUND
Collaterals are arteriole-to-arteriole anastomoses that connect adjacent arterial trees. They lessen ischemic tissue injury by serving as endogenous bypass vessels when the trunk of 1 tree becomes narrowed by vascular disease. The number and diameter ("extent") of native (preexisting) collaterals, plus their amount of lumen enlargement (growth/remodeling) in occlusive disease, show remarkably wide variation among inbred mouse strains (eg, C57BL/6 and BALB/c), resulting in large differences in tissue injury in models of occlusive disease. Evidence suggests similar large differences exist among healthy humans.


OBJECTIVE
To identify candidate loci responsible for genetic-dependent collateral variation.


RESULTS
Cerebral collateral number and diameter were determined in 221 C57BL/6xBALB/c F2 progeny, followed by linkage analysis to identify quantitative trait loci (QTL) for collateral number and diameter. Four QTL were obtained for collateral number, including epistasis between 2 loci. A QTL that was identical to the strongest QTL for collateral number on chromosome 7 (logarithm of the odds [LOD]=29, effect size=37%) was also mapped for collateral diameter (LOD=17, effect size=30%). Chromosome substitution strain analysis confirmed this locus. We also obtained a unique QTL on chromosome 11 for collateral remodeling after middle cerebral artery occlusion. Association mapping within the chromosome 7 QTL interval using collateral traits measured for 15 inbred strains delineated 172-kbp (P=0.00002) and 290-kbp (P=0.0004) regions on chromosome 7 containing 2 and 7 candidate genes, respectively.


CONCLUSIONS
We conclude that collateral extent and remodeling are unique, highly heritable complex traits, with 1 QTL predominantly affecting native collateral number and diameter.
Wang
Shiliang
S
Department of Cell and Molecular Physiology and the McAllister Heart Institute, University of North Carolina at Chapel Hill, NC 27599-7545, USA.
Zhang
Hua
H
Dai
Xuming
X
Sealock
Robert
R
Faber
James E
JE
D000818:Animals; D001921:Brain / Q000098:blood supply*; D001931:Brain Mapping / Q000379:methods; D003097:Collateral Circulation / Q000235:genetics*; D003433:Crosses, Genetic; D008040:Genetic Linkage / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000473:pathology; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D040641:Quantitative Trait Loci / Q000235:genetics; D013045:Species Specificity