Endothelial plasticity in cardiac repair after myocardial infarction

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Project Summary Ischemic heart disease is the most common cause of death in the western world, largely due to myocardial infarction (MI), the irreversible damage of myocardial tissue induced by the blockage in coronary arteries. After MI, formation of new blood vessels, i.e., neovascularization, is crucial for ischemic tissue reperfusion and repair. However, the newly formed vasculatures in infarcted tissue are characterized by functional and structural abnormalities, which compromise vessel delivery function and cardiac repair after MI. Likewise, aberrant non-productive neovascularization represents a promising therapeutic target for MI treatment. Here, by utilizing endothelial lineage tracing and single-cell RNAseq technology, our preliminary studies with a murine MI model reveal robust endothelial cell (EC) plasticity mediated through endothelial mesenchymal transformation (Endo-MT, i.e., partial endothelial mesenchymal transition) during cardiac repair after MI. We show that ECs acquire mesenchymal phenotypes including high proliferation and motility after MI, leading to vascular abnormalities and non-productive neovascularization. We identify a PDGF/NF- kB/HIF-1a/Snail-mediated axis that controls Endo-MT. Notably, EC-specific deletion of PDGF receptor-b promotes post-MI tissue repair and cardiac function recovery in mice. Finally, pharmacological inhibition of PDGF improves cardiac function recovery after MI. In addition, Snail is expressed in human MI-associated ECs. Based on these findings, we hypothesize that endothelial plasticity drives non-productive neovascularization and impedes cardiac repair after MI. To test this hypothesis, we will pursue the following aims: 1) To define the molecular mechanisms for endothelial plasticity after MI; 2) To determine the in vivo role of endothelial plasticity for aberrant neovascularization and cardiac repair after MI; and 3) To test experiment therapy that targets PDGFR-mediated endothelial plasticity for MI treatment. Thus, targeting EC plasticity may offer a promising therapeutic opportunity to recondition vascular microenvironment and improve cardiac repair and function recovery after MI. Successful completion of this project will provide new insights into the mechanism for aberrant neovascularization and may lead to development of new therapeutic revenue for treating ischemic heart disease.