Implication of collateral growth in the process of cardiac regeneration after neonatal infarction in mice

Abstract

The recent discovery of the capacity of the mammalian heart to completely regenerate during a short period of time after birth opened a new area of research in the cardiovascular field. The revascularization of the ischemic area is an important process to favor cardiac regeneration and we have previously shown that preexisting coronary arteries undergo major remodeling events following adult MI. This mechanism of arteriogenesis is known as collateral growth but it has not been well described during cardiac regeneration. We hypothesize that collateral growth occurs more frequently in regenerative hearts compared to non-regenerative ones. To investigate the coronary arteries remodeling and collateral growth during cardiac regeneration after neonatal myocardial infarction (MI). Neonatal MI was performed by the permanent ligation of the left coronary artery on one day-old (P1) and seven day-old (P7) mice. MI surgery was performed on P1 or P7 pups from the Cx40-GFP mouse line in which the fluorescent protein GFP is specifically expressed in coronary arteries. Hearts were collected at 1, 2, 4, 7 and 14 dpi and processed for clearing using CUBIC solution. 3D reconstruction was acquired from images of cleared hearts. Our data show the dynamic remodeling of the ligated coronary artery, which completely regenerates in two weeks, starting one day-post-injury (dpi) by the migration of isolated arterial endothelial cells migrating from the injured artery to form a new vessel at 4dpi. We observed a larger number of collaterals branching from the injured left artery to healthy right or septal arteries in regenerating hearts (P1) in comparison with non-regenerating hearts (P7). These results highlight the rapid phase of arterial remodeling that would play an important role in inducing cardiac regeneration.