Endothelial Plasticity Drives Arterial Remodeling Within the Endocardium After Myocardial Infarction

Rationale: Revascularization of injured, ischemic, and regenerating organs is essential to restore organ function. In the postinfarct heart, however, the mechanisms underlying the formation of new coronary arteries are poorly understood. Objective: To study vascular remodeling of coronary arteries after infarction. Methods and Results: We performed permanent left coronary ligation on Connexin40-GFP mice expressing green fluorescent protein ( GFP ) in endothelial cells of coronary arteries but not veins, capillaries, or endocardium. GFP + endothelial foci were identified within the endocardium in the infarct zone. These previously undescribed structures, termed endocardial flowers, have a distinct endothelial phenotype (Cx40 + , VEGFR2 + , and endoglin − ) to the surrounding endocardium (Cx40 − , VEGFR2 − , and endoglin + ). Endocardial flowers are contiguous with coronary vessels and associated with subendocardial smooth muscle cell accumulation. Genetic lineage tracing reveals extensive endothelial plasticity in the postinfarct heart, showing that endocardial flowers develop by arteriogenesis of Cx40 − cells and by outgrowth of pre-existing coronary arteries. Finally, endocardial flowers exhibit angiogenic features, including early VEGFR2 expression and active proliferation of adjacent endocardial and smooth muscle cells. Conclusions: Arterial endothelial foci within the endocardium reveal extensive endothelial cell plasticity in the infarct zone and identify the endocardium as a site of endogenous arteriogenesis and source of endothelial cells to promote vascularization in regenerative strategies.