Congenic Fine-Mapping Identifies a Major Causal Locus for Variation in the Native Collateral Circulation and Ischemic Injury in Brain and Lower Extremity

Abstract

Rationale Severity of tissue injury in occlusive disease is dependent on the extent (number and diameter) of collateral vessels, which varies widely among healthy mice and humans. However, the causative genetic elements are unknown. Recently, much of the variation among different mouse strains, including C57Bl/6J (B6, high extent) and BALB/cByJ (Bc, low), was linked to a QTL on chromosome 7 (Candq1). Objective We used congenic mapping to refine Candq1 and its candidate genes and create an “isogenic” strain-set with large differences in collateral extent to assess their and Candq1’s impact, alone, on ischemic injury. Methods and Results Six congenic strains possessing portions of Candq1 introgressed from B6 into Bc were generated and phenotyped. Candq1 was refined from 27 to 0.737 Mb with full retention of effect, ie, return/rescue of phenotypes from the poor values in Bc to nearly those of wildtype B6 in the B6/B6 congenic mice: 83% rescue of low pial collateral extent, and 4.5-fold increase in blood flow and 85% reduction of infarct volume after middle cerebral artery occlusion; 54% rescue of low skeletal muscle collaterals, and augmented recovery of perfusion (83%) and function after femoral artery ligation. Gene deletion and in-silico analysis further delineated the candidate genes. Conclusion We have significantly refined Candq1 (now designated Determinant of collateral extent-1, Dce1), demonstrated that genetic background-dependent variation in collaterals is a major factor underlying differences in ischemic tissue injury, and generated a congenic strain-set with wide, allele-dose-dependent variation in collateral extent for use in investigations of the collateral circulation.

Endothelial fluid shear stress sensing in vascular health and disease

“…In mice, different strains exhibit striking variation in the extent of remodeling and recovery following femoral artery ligation (101). Genetic mapping comparing the two strains at the extremes of the distribution for collateral arteriogenesis restrained the possible differences to a few genetic loci, though no candidate gene that explains the differences has been identified (102). Hypercholesterolemia (103,104), obesity (105), and aging (106) also compromise arteriogenesis in mouse models.…”

Collateral blood vessels in acute ischemic stroke: a physiological window to predict future outcomes

“…{Zhang, 2010 #110} A single polymorphic locus on chromosome 7 in mice, i.e., the determinant of collateral extent 1 (Dce1), has been shown to influence the extent of collateralization, blood flow and infarct volume after middle cerebral artery occlusion 22 . Whether human Dce1 or related loci are responsible for the wide variation in collateral status in humans is still under investigation.…”

Collateral Development

“…In this issue of Circulation Research, Sealock et al 19 further our understanding of the genetic basis of collateralization in the brain and peripheral circulation through congenic mapping of a 27 Mb region on mouse chromosome 7 (Candq1) attributed to strain-dependent differences in innate collateral vessel diameter and number. Candq1 is located within a region containing other QTLs (Civq-5, Lsq-1) associated with differences in hindlimb perfusion and cerebral infarct volumes but does not share candidate gene targets with these loci.…”

“…Candq1 is located within a region containing other QTLs (Civq-5, Lsq-1) associated with differences in hindlimb perfusion and cerebral infarct volumes but does not share candidate gene targets with these loci. 19 This divergence identified a need to refine and reconcile QTLs identified indirectly by ischemia with those identified by structural characteristics to the same physiological process (ie, collateralization). Congenic lines were developed by introgressing sections of Candq1 from c57bl/6 mice, a collateral-rich strain, to the background of BalbC, a collateral-poor strain.…”

“…I think that Sealock et al 19 have made a significant advancement by shifting our focus in a promising new direction toward membrane trafficking. I look forward to the next chapter in this collateral saga.…”