The transient formation of collaterals contributes to the restoration of the arterial tree during cardiac regeneration

Abstract Revascularization of ischemic myocardium following cardiac damage is an important step in cardiac regeneration. We have previously shown that pre-existing coronary arteries undergo major remodeling events following myocardial infarction (MI) in adult mouse hearts. The mechanism of arteriogenesis has not been well described during cardiac regeneration. Here we investigated a follow up of coronary artery remodeling and collateral growth during cardiac regeneration. Neonatal MI was induced by ligature of the left descending artery (LAD) in postnatal day (P) 1 or P7 pups from the Cx40-GFP mouse line in which GFP is expressed in coronary arterial endothelial cells. The arterial tree was reconstructed in 3D from images of cleared hearts collected at 1, 2, 4, 7 and 14 days after infarction. Our data show a rapid remodeling of the left coronary arterial tree induced by neonatal MI and the formation of numerous collateral arteries, which are transient in regenerating hearts after MI at P1 and persistent in non-regenerating hearts after MI at P7. This difference is accompanied by restoration of a perfused or a non-perfused LAD following MI at P1 or P7 respectively. Interestingly, we found that perfusion precedes collateral growth and lineage tracing analysis demonstrates that the restoration of the LAD occurs by remodeling of arterial cells. These results demonstrate that the restoration of the LAD artery during cardiac regeneration occurs by pruning with the rapid formation of collaterals supporting perfusion of the disconnected lower LAD which subsequently disappear on restoration of a unique LAD. These results highlight a rapid phase of arterial remodeling that plays an important role in vascular repair during cardiac regeneration.