Endothelial Plasticity Drives Arterial Remodeling Within the Endocardium Following Myocardial Infarction
Rationale: Revascularization of injured, ischemic and regenerating organs is essential to restore organ function. In the post-infarct heart, however, the mechanisms underlying the formation of new coronary arteries are poorly understood.
Objective: To study vascular remodeling of coronary arteries following infarction.
Methods and Results: We performed permanent left coronary ligation on Connexin40-GFP mice expressing 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+ and VEGFR2+, Endoglin-) to the surrounding endocardium (Cx40- and VEGFR2-, Endoglin+). Endocardial flowers are contiguous with coronary vessels and associated with sub-endocardial smooth muscle cell accumulation. Genetic lineage tracing reveals extensive endothelial plasticity in the post-infarct heart, showing that endocardial flowers develop by arteriogenesis of Cx40- cells as well as 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.
- cell plasticity
- endothelial cell differentiation
- myocardial infarction
- vascular remodeling
- Received March 18, 2015.
- Revision received March 26, 2015.
- Accepted April 1, 2015.