Wide Genetic Variation in the Native Pial Collateral Circulation is a Major Determinant of Variation in Severity of Stroke

Abstract

Severity of stroke varies widely among individuals. Whether differences in the extent of the native (preexisting) pial collateral circulation exist and contribute to this variability is unknown. We addressed these questions and probed for potential genetic contributions using morphometric analysis of the collateral circulation in 15 inbred mouse strains recently shown to exhibit wide differences in infarct volume. Morphometrics were determined in the unligated left hemisphere (for native collaterals) and ligated right hemisphere (for remodeled collaterals) 6 days after permanent middle cerebral artery (MCA) occlusion. Variation among strains in native collateral number, diameter, MCA, anterior cerebral artery (ACA), and posterior cerebral artery (PCA) tree territories were, respectively: 56-fold, 3-fold, 42%, 56%, and 61%. Collateral length ( P<0.001) and the number of penetrating arterioles branching from them also varied ( P<0.05). Infarct volume correlated inversely with collateral number ( P<0.0001), diameter ( P<0.0001), and penetrating arteriole number ( P<0.05) and directly with MCA territory ( P<0.05). Relative collateral conductance and MCA territory, when factored together, strongly predicted infarct volume ( P<0.0001). Outward remodeling of collaterals in the ligated hemisphere varied ∼3-fold. These data show that the extent of the native pial collateral circulation and collateral remodeling after obstruction vary widely with genetic background, and suggest that this variability, due to natural polymorphisms, is a major contributor to variability in infarct volume.