Abstract
Restoring blood flow after myocardial infarction (MI) is essential for survival of existing and newly regenerated tissue. Endogenous vascular repair processes are deployed following injury but are poorly understood. We sought to determine whether developmental mechanisms of coronary vessel formation are intrinsically reactivated in the adult mouse after MI. Using pulse-chase genetic lineage tracing, we establish that de novo vessel formation constitutes a substantial component of the neovascular response, with apparent cellular contributions from the endocardium and coronary sinus. The adult heart reverts to its former hypertrabeculated state and repeats the process of compaction, which may facilitate endocardium-derived neovascularization. The capacity for angiogenic sprouting of the coronary sinus vein, the adult derivative of the sinus venosus, may also reflect its embryonic origin. The quiescent epicardium is reactivated and, while direct cellular contribution to new vessels is minimal, it supports the directional expansion of the neovessel network toward the infarcted myocardium. Thymosin β4, a peptide with roles in vascular development, was required for endocardial compaction, epicardial vessel expansion, and smooth muscle cell recruitment. Insight into pathways that regulate endogenous vascular repair, drawing on comparisons with development, may reveal novel targets for therapeutically enhancing neovascularization.
Highlights
Reperfusion therapy limits the duration of ischemia and the extent of myocardial loss, adverse remodeling, and progression to heart failure
We initially examined the vascular response in murine hearts following permanent ligation of the left anterior descending coronary artery (LAD) across a time course
Our study provides descriptive evidence to support the apparent recapitulation of developmental mechanisms, with roles for all three recognized embryonic endothelial cells (ECs) sources, toward neovascularization of the ischemic adult heart
Summary
Reperfusion therapy limits the duration of ischemia and the extent of myocardial loss, adverse remodeling, and progression to heart failure. Angiogenic growth factor therapy has demonstrated minimal efficacy in clinical trials [2, 3], and progenitor cell transplantation approaches are hindered by limited engraftment and trans-differentiation, they have proven paracrine benefits [4]. These failures betray both a lack of understanding of the endogenous neovascularization that occurs in the heart in response to ischemic injury and an appreciation of the processes that underlie the establishment of a hierarchical vascular network, as occurs during development. It has been assumed that new vessels derive exclusively via angiogenesis [5], alongside collateral growth [6]
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