Abstract
BackgroundNative (pre-existing) collaterals are arteriole-to-arteriole anastomoses that interconnect adjacent arterial trees and serve as endogenous bypass vessels that limit tissue injury in ischemic stroke, myocardial infarction, coronary and peripheral artery disease. Their extent (number and diameter) varies widely among mouse strains and healthy humans. We previously identified a major quantitative trait locus on chromosome 7 (Canq1, LOD = 29) responsible for 37% of the heritable variation in collateral extent between C57BL/6 and BALB/c mice. We sought to identify candidate genes in Canq1 responsible for collateral variation in the cerebral pial circulation, a tissue whose strain-dependent variation is shared by similar variation in other tissues.Methods and FindingsCollateral extent was intermediate in a recombinant inbred line that splits Canq1 between the C57BL/6 and BALB/c strains. Phenotyping and SNP-mapping of an expanded panel of twenty-one informative inbred strains narrowed the Canq1 locus, and genome-wide linkage analysis of a SWRxSJL-F2 cross confirmed its haplotype structure. Collateral extent, infarct volume after cerebral artery occlusion, bleeding time, and re-bleeding time did not differ in knockout mice for two vascular-related genes located in Canq1, IL4ra and Itgal. Transcript abundance of 6 out of 116 genes within the 95% confidence interval of Canq1 were differentially expressed >2-fold (p-value<0.05÷150) in the cortical pia mater from C57BL/6 and BALB/c embryos at E14.5, E16.5 and E18.5 time-points that span the period of collateral formation.ConclusionsThese findings refine the Canq1 locus and identify several genes as high-priority candidates important in specifying native collateral formation and its wide variation.
Highlights
Ischemic stroke, myocardial infarction and atherosclerotic disease of arteries supplying the brain, heart and lower extremities are leading causes of morbidity and mortality
We previously identified a prominent QTL on chromosome 7 (Canq1, LOD = 29) responsible for 37% of the heritable variation in collateral extent in the cerebral circulation of C57BL/6 and BALB/c mice [15]—strains which exhibit the widest difference among 15 strains examined [9]
Given the unique mosaic genetic structure for each recombinant inbred lines (RILs), we hypothesized that if Canq1 in general, and the ‘‘EMMA region’’ [15] in particular, are determinants of collateral extent, an RIL that inherits this locus from either B6 or Bc [8,9,10,15] will exhibit traits dominated by the parental phenotype
Summary
Myocardial infarction and atherosclerotic disease of arteries supplying the brain, heart and lower extremities are leading causes of morbidity and mortality. Variation in the density and diameter (extent) of the native pre-existing collaterals present in a tissue have become recognized as important determinants of the wide variation in severity of tissue injury caused by these diseases [1,2,3,4]. Native (pre-existing) collaterals are arteriole-to-arteriole anastomoses that interconnect adjacent arterial trees and serve as endogenous bypass vessels that limit tissue injury in ischemic stroke, myocardial infarction, coronary and peripheral artery disease. Their extent (number and diameter) varies widely among mouse strains and healthy humans. We sought to identify candidate genes in Canq responsible for collateral variation in the cerebral pial circulation, a tissue whose strain-dependent variation is shared by similar variation in other tissues
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