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

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

Nature cardiovascular research (2022-05-17)
Menggui Huang, Fan Yang, Duo Zhang, Maohuan Lin, Hao Duan, Rakan El-Mayta, Lin Zhang, Ling Qin, Swapnil V Shewale, Liming Pei, Michael J Mitchell, Daniel J Rader, Yi Fan, Yanqing Gong
ABSTRACT

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 signature that result in phenotypic and functional changes and lead to vessel abnormalities. We identify a PDGF/NF-κB/HIF-1α axis that induces Snail expression and mesenchymal phenotypes in ECs under hypoxia, altogether causing aberrant vascularization. EC-specific knockout of PDGFR-β, pharmacological PDGFR inhibition or nanoparticle-based targeted PDGFR-β siRNA 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cytosine β-D-arabinofuranoside hydrochloride, crystalline
Sigma-Aldrich
Deoxyribonuclease I from bovine pancreas, Type II, lyophilized powder, Protein ≥80 %, ≥2,000 units/mg protein
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Fetal Bovine Serum, USA origin, sterile-filtered, suitable for cell culture, suitable for hybridoma
Sigma-Aldrich
Anti-SNAI1 Antibody, clone 10H4.1, clone 10H4.1, from mouse
Sigma-Aldrich
L-Cysteine, from non-animal source, BioReagent, suitable for cell culture, ≥98%