Endothelial plasticity drives aberrant vascularization and impedes cardiac repair after myocardial infarction

Myocardial infarction (MI) is a leading cause of death worldwide, largely because efficient interventions to restore cardiac function after MI are currently lacking. Here, we characterize vascular aberrancies induced by MI and propose to target acquired endothelial cell (EC) changes to normalize vessels and promote cardiac repair after MI. Single-cell transcriptome analyses of MI-associated ECs indicates that ECs acquire mesenchymal gene signatures that result in phenotypic and functional changes and lead to vessel abnormalities. We identify a platelet-derived growth factor (PDGF)–nuclear factor κB (NF-κB)–hypoxia-inducible factor 1-α (HIF-1α) axis that induces Snail expression and mesenchymal phenotypes in ECs under hypoxia, altogether causing aberrant vascularization. EC-specific knockout of platelet-derived growth factor receptor beta (PDGFR-β), pharmacological PDGFR inhibition or nanoparticle-based targeted PDGFR-β small interfering RNA delivery in mice attenuates vascular abnormalities in the infarcted tissue and improves cardiac repair after MI. These findings illustrate a mechanism controlling aberrant neovascularization after ischemia and suggest that targeting PDGF/Snail-mediated endothelial plasticity may offer opportunities for normalizing vasculature and treating ischemic heart diseases. Huang et al. show that myocardial infarction (MI)-associated vasculature is structurally and functionally abnormal, impeding vessel function and cardiac repair in mice. Analyses of the transcriptome of the cardiac endothelium after MI identify a PDGF–NF-κB–HIF-1α Snail axis responsible for mesenchymal transformation of endothelial cells and show that genetic ablation or targeted disruption of PDGF signaling normalizes vasculature and improves cardiac function recovery after MI.