Abstract 679: Pdgf/snail-mediated Endothelial Plasticity Drives Non-productive Neovascularization and Impedes Tissue Repair After Myocardial Infarction

Ischemic heart disease is the most common cause of death in the Western world, largely due to myocardial infarction (MI). After MI, formation of new blood vessels, i.e. , neovascularization, is crucial for ischemic tissue reperfusion, repair and regeneration. However, the newly formed vasculatures in infarcted tissue are characterized by functional and structural abnormalities, which compromise vascular delivery function and impede cardiac recovery after MI. Likewise, aberrant non-productive neovascularization, albeit previously under-appreciated, represents a promising therapeutic target for post-MI treatment. Here we reveal that mesenchymal transformation-mediated endothelial cell (EC) plasticity induces aberrant post-ischemic neovascularization. In contrast to the old concept implicating that ECs undergo endothelial mesenchymal transitions to generate fibroblasts de novo in infarcted cardiac tissue, we suggest that ECs acquire mesenchymal phenotypes including high proliferation and motility to generate excessive abnormal vasculatures after MI. By utilizing genetic EC lineage tracing and single-cell RNAseq technologies with a mouse MI model induced by ligation of left anterior descending coronary artery, our transcriptome analysis uncovers that ECs undergo mesenchymal transformation in infarcted tissues. Moreover, exposure of cardiac ECs to ischemic microenvironment in vitro induces EC expression of mesenchymal genes including S100A4, ACTA2, and CDH2, and interestingly, EC functions including tube formation and uptake of ac-LDL are retained, suggesting EC mesenchymal transformation without lineage transition. Furthermore, we identify a PDGF/Snail-mediated axis that controls EC transformation under hypoxia. Notably, genetic ablation of PDGF receptor-β in ECs promotes blood perfusion and tissue repair after hindlimb ischemia and MI in mice. These findings identify a novel cellular mechanism controlling non-productive neovascularization after ischemia, and suggest that targeting EC plasticity may offer promising therapeutic opportunities for normalization of aberrant neovasculature and improvement of tissue repair in ischemic heart diseases.