Strain-dependent variation in collateral circulatory function in mouse hindlimb

The extent (density and diameter) of the native (preexisting) collateral circulation in healthy tissues and the capacity of collaterals to enlarge/remodel in obstructive arterial disease are important determinants of ischemic injury. Evidence suggests that these parameters vary widely from yet-to-be-identified genetic and environmental factors. Recently, a locus on chromosome 7 was linked to less recovery of perfusion after femoral artery ligation in BALB/c and A/J versus C57BL/6 mouse strains. Moreover, evidence suggested that BALB/c and A/J share an allele(s) at this locus that is different from C57BL/6 mice. Here we tested the hypothesis that differences in collateral extent and/or remodeling underlie these findings. Compared with C57BL/6, BALB/c and A/J strains have fewer native collaterals in hindlimb (also confirmed in brain)-associated with greater reduction in perfusion immediately after femoral ligation, slower recovery of perfusion, greater hindlimb use impairment, and worse ischemia. However, A/J also differed from BALB/c in a number of these parameters, including having more robust collateral remodeling. Analysis of A/J --> C57BL/6 chromosome substitution strains confirmed that a difference in an allele(s) on chromosome 7 conferred most, but not all, of the magnitude of the differences in collateral function. Additional studies of C57BL/6 x BALB/c F1 mice demonstrated that alleles of the C57BL/6 strain exert dominance for collateral traits. Finally, negative results were obtained from studies examining a previously identified candidate gene potentially responsible for these differences-Bcl2-associated athanogene-3. These findings emphasize the major contribution of genetic background to variation in the collateral circulation and its capacity to lessen ischemia in obstructive disease.