Abstract
Variation in extent of the native pre-existing collateral (COL) circulation, ie, COL number and average diameter in healthy tissues, is a major determinant of the variation in severity of tissue injury after acute obstruction. Indirect evidence suggests that coronary COL extent varies widely in presumed healthy humans. Although the cause of this variation is unknown, studies in non-heart tissues of healthy mouse strains have found that differences in genetic background are a major determinant. Whether this applies to the heart is unknown, because no model exists to investigate the coronary COL circulation in mice. In addition, little is known regarding whether new COLs can be induced to form in individuals with few native COLs. To address these questions, we developed a mouse model that combines high-resolution (capillary-level) microangiography and ligation (LADX) with measurement of coronary COL conductance index and infarct volume. Adult (3-mos-old) mouse strains chosen for their large rank-order difference in native COL extent in brain and hindlimb-BLKS > C57BL/6 > A > BALB/c-all lack native coronary COLs. After LADX, all strains formed new COLs by day-3 that reached maximum number and diameter by day-14. However, rank-order for new COL formation differed from the above, ie, C57BL/6 @ BALB/c > BLKS > A; COL conductance and infarct volume -1 followed this same rank-order. Moreover, the rank-order for new COL formation differed from the rank-order for COL remodeling after arterial ligation in brain and hindlimb, ie, A > C57BL/6 > BALB/c. Ongoing studies to determine the mechanisms of new COL formation after LADX find strongly reduced COL formation and conductance and increased infarct volume in C57BL/6 mice deficient in monocyte chemoattractant protein-1 or its receptor (CCR2)-effects partially rescued by bone marrow transplantation. Conclusions: Unlike other tissues, the mouse heart lacks native COLs. Mice thus provide a model to study coronary collaterogenesis free of complications posed by remodeling of pre-existing COLs. Gene polymorphisms underlying variation in ischemic coronary collaterogenesis differ from those underlying variation in embryonic formation of native COLs. MCP-1 and bone marrow cells play an important role in new COL formation.
Published Version
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