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Principal Investigator: Yi Fan
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $588,825
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <7B4 Antigen><7B4 protein><Angiogenesis Factor><Angiogenic Factor><Anterior Descending Coronary Artery><Basal Transcription Factor><Basal transcription factor genes><Biology><Biomedical Engineering><Blood Vessels><Body Tissues><CD140B><CD140b Antigens><CD144 Antigen><Cancers><Cardiac><Cardiac artery><Cardiac infarction><Cardiology><Cause of Death><Cell Body><Cell Growth in Number><Cell Lineage><Cell Locomotion><Cell Migration><Cell Movement><Cell Multiplication><Cell Proliferation><Cells><Cellular Migration><Cellular Motility><Cellular Proliferation><Clinic><Clonal Expansion><Closure by Ligation><Coronary artery><Development><Echocardiogram><Echocardiography><Embryo Development><Embryogenesis><Embryonic Development><Endothelial Cells><Endothelium><Ensure><Exhibits><Experimental Therapies><Fibroblasts><Fibrosis in the heart><Fibrosis in the myocardium><Fibrosis within the heart><Fibrosis within the myocardium><Fibrotic myocardium><Gene Action Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioma><Goals><Growth><HIF 1 alpha><HIF-1alpha><HIF1-Alpha><HIF1A><HIF1A gene><HIF1α><Heart Muscle tissue><Heart artery><Heart failure><Human><Immunoglobulin Enhancer-Binding Protein><In Vitro><Infarction><Inflammation><Interdisciplinary Research><Interdisciplinary Study><Investigational Therapies><Investigational Treatments><Investigators><Ischemia><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><JTK12><KO mice><Kinases><Knock-out Mice><Knockout Mice><Left><Leiomyocyte><Ligation><MOP1><Malignant Neoplasms><Malignant Tumor><Mediating><Mesenchymal><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Motility><Multidisciplinary Collaboration><Multidisciplinary Research><Murine><Mus><Myocardial Infarct><Myocardial Infarction><Myocardial Ischemia><Myocardial tissue><NF-kB><NF-kappa B><NF-kappaB><NFKB><Nature><Neuroglial Neoplasm><Neuroglial Tumor><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Null Mouse><Outcome><PDGF><PDGF Receptor β><PDGF Receptors><PDGF beta Receptor><PDGF inhibition><PDGF β Receptor><PDGF-R-Beta><PDGFR><PDGFR beta><PDGFR-β><PDGFR1><PDGFRB><PDGFRB gene><Pathologic><Phase><Phenotype><Phosphotransferase Gene><Phosphotransferases><Platelet-Derived Growth Factor><Platelet-Derived Growth Factor Receptor><Platelet-Derived Growth Factor Receptor Beta Polypeptide><Platelet-Derived Growth Factor Receptor β><Platelet-Derived Growth Factor beta Receptor><Proliferating><Proteins><Recovery><Recovery of Function><Reperfusion Therapy><Research Personnel><Researchers><Role><Science><Short interfering RNA><Small Interfering RNA><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Snails><Structural defect><Structural malformation><Structure><Technology><Testing><Therapeutic><Time><Tissue Growth><Tissues><Transcription Factor NF-kB><Transcription Factor Proto-Oncogene><Transcription factor genes><Transphosphorylases><Transthoracic Echocardiography><VE-Cadherin><VEGF><VEGFs><Vascular Endothelial Cadherin><Vascular Endothelial Cadherin 1><Vascular Endothelial Growth Factors><Vascularization><Western World><Work><angiogenesis><bio-engineered><bio-engineers><bioengineering><biological engineering><blood perfusion><blood vessel development><blood vessel formation><cadherin 5><cancer microenvironment><cardiac failure><cardiac fibrosis><cardiac function><cardiac infarct><cardiac ischemia><cardiac repair><cell motility><coronary attack><coronary fibrosis><coronary infarct><coronary infarction><coronary ischemia><developmental><experimental therapeutic agents><experimental therapeutics><fibrotic heart><function of the heart><functional recovery><glial-derived tumor><global gene expression><global transcription profile><heart attack><heart fibrosis><heart function><heart infarct><heart infarction><heart ischemia><heart repair><heart sonography><improved><in vivo><infarct><inhibitor><insight><kappa B Enhancer Binding Protein><malignancy><mortality><myocardial damage><myocardial fibrosis><myocardial ischemia/hypoxia><myocardium ischemia><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><neovascularization><neuroglia neoplasm><neuroglia tumor><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nuclear factor kappa beta><ontogeny><pharmacologic><progenitor-like cell><repair><repair function><repaired><reparative function><reperfusion><restoration><scRNA-seq><siRNA><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stem-like cell><structural abnormalities><structural anomalies><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tissue repair><transcription factor><transcriptome><trend><tumor microenvironment><vascular><vascular abnormality>