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Abstract
Introduction Restoring blood flow after myocardial infarction (MI) is essential for the oxygenation of existing and newly regenerated tissue. Proangiogenic therapies have been previously investigated in an attempt to target existing coronary vessels, but with limited success. Endogenous vascular repair processes are poorly understood, therefore we sought to determine whether coronary vessel developmental mechanisms are intrinsically reactivated following injury in the adult mouse heart. During development, the endocardium contributes 60% of coronary vessels, in large part via compaction of the trabeculated endocardial surface perinatally. We therefore extended consideration to the endocardium as a source of de novo vessels in the adult MI setting.
Methods MI was induced in mice using LAD ligation,and pulse-chase genetic lineage tracing was utilised to investigate the source of sub-endocardial vessels in the ischemic adult heart. In order to gain insight into the mechanisms that regulate endocardium-derived vessel formation, we investigated candidate signalling pathways which orchestrate trabeculation and compaction during development. Following these preliminary analyses, a Notch1 loss-of-function model was generated to interrogate a potential role for Notch1 in endocardial remodelling and neovascularisation post-MI.
Results We demonstrated that the adult heart reverts to a hypertrabeculated state between 1 and 5 days post-MI and repeats the process of endocardial compaction from 7–14 days. This process appears to facilitate endocardium-derived neovascularization, leading to formation of mature sub-endocardial vessels after infarction. We observed reactivation of the Notch pathway in the endocardium following MI, in keeping with its role as a key regulator of these processes in development. Using a Notch1 loss-of-function mouse model targeted by an endothelial-specific Cre, we observed impaired trabeculation with reduced sub-endocardial vessel count after disruption of Notch activity. (Figure 1)
Abstract BS1 Figure 1
Conclusion We established that de novo vessel formation constitutes a significant component of the neovascular response and revealed that the endocardium is a major contributory source. Notch1 was identified as a key driver in this remodelling process and, moreover, our data suggest a role for Notch in driving endothelial-mesenchymal transition (EndMT) to provide smooth muscle support to newly formed vessels. Ongoing work seeks to determine whether targeting trabeculation in the adult heart will contribute to improved neovascularisation post-MI.
Conflict of interest N/A