Abstract 5108: Variation in Pial Collaterals in 15 Mouse Strains is a Major Determinant of Infarct Volume After Middle Cerebral Artery Occlusion (MCAO)
The importance of vascular, non-vascular and genetic factors in the wide variability in severity of infarct volume (IV) is unclear. We have reported previously that density and diameter of native collaterals in tissues vary widely with genetic background. The purpose of this study was to determine the contribution of genetic variation in collaterals to variation in IV in a cohort of genetic reference strains. IV was determined 1 day after MCAO. In a second set of mice, the vasculature was dilated, fixed and cast 6 days after MCAO. The number and diameter of pial collaterals were determined for the unligated left and ligated right hemispheres, as were territories of the MCA, ACA and PCA trees. Variations among strains in IV, native collateral number and diameter, and MCA, ACA and PCA territories were, respectively: 30-fold, 56-fold, and 3-fold, and 42%, 56% and 61%. IV and collateral dimensions did not correlate with brain size or PCA territory, but IV correlated highly with collateral number and diameter ((p<0.0001), and less so with MCA (p<0.05) and ACA territory (p<0.01). Arrangement of these parameters (excepting IV) into an expression of collateral conductance strongly predicted IV (p<0.0001). Prediction was improved by factoring in collateral length and hematocrit. There was no correlation between MCA territory and collateral number or diameter, suggesting genetic determinants of tree territory do not specify collateral dimensions. However, collateral dimensions were highly inter-correlated, suggesting they could arise from common genetic variants. Increase in collateral diameter on the ligated side (remodeling) varied by more than 2-fold and correlated with collateral diameter (p<0.0001) and number (p<0.01). Genome-wide haplotype and C57BL/6 × BALB/cBy F2 mapping are underway to identify potential loci harboring variants important in collateral formation. These data suggest that conductance of the pial collateral circulation is the primary determinant of stroke severity, and that polymorphisms in genes specifying formation of the native collateral circulation and its remodeling in ischemia are important determinants of stroke risk and stroke variance. These findings may generalize to heart, limb and other tissues.