Endothelial plasticity in cardiac repair after myocardial infarction

心肌梗死后心脏修复中的内皮可塑性

• 批准号: 10467987
• 负责人: Yi Fan
• 金额: $ 60.08万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-11 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467987
• 关键词: Angiogenic Factor; Anterior Descending Coronary Artery; Biology; Biomedical Engineering; Blood Vessels; Cardiac; Cardiology; Cause of Death; Cell Lineage; Cell Proliferation; Cells; Clinic; Clonal Expansion; Coronary artery; Development; Echocardiography; Endothelial Cells; Endothelium; Ensure; Exhibits; Fibroblasts; Gene Expression Regulation; Gene Proteins; Genetic; Glioma; Goals; Growth; Heart; Heart failure; Human; In Vitro; Inflammation; Interdisciplinary Study; Ischemia; Knockout Mice; Lead; Left; Ligation; Malignant Neoplasms; Mediating; Mesenchymal; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; NF-kappa B; Nature; Outcome; PDGF inhibition; PDGFRB gene; Pathologic; Perfusion; Pharmacology; Phase; Phenotype; Phosphotransferases; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor beta Receptor; Proteins; Recovery; Recovery of Function; Reperfusion Therapy; Research Personnel; Role; Science; Small Interfering RNA; Smooth Muscle Myocytes; Snails; Structural defect; Structure; Technology; Testing; Therapeutic; Time; Tissues; Vascular Endothelial Growth Factors; Vascularization; Western World; Work; angiogenesis; base; blood perfusion; blood vessel development; cadherin 5; cardiac repair; cell motility; coronary fibrosis; experimental study; heart function; hypoxia inducible factor 1; improved; in vivo; inhibitor; insight; mortality; myocardial damage; nanoparticle; neovascularization; novel therapeutics; repair function; repaired; restoration; single-cell RNA sequencing; stem-like cell; targeted treatment; therapeutic target; tissue repair; transcription factor; transcriptome; trend; vascular abnormality

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.

项目摘要 缺血性心脏病是西方世界最常见的死亡原因，主要是由于心肌梗死。 心肌梗死（MI）是由冠状动脉阻塞引起的心肌组织的不可逆损伤， 动脉MI后，新血管形成，即，新血管形成对于缺血组织至关重要 再灌注和修复。然而，梗塞组织中新形成的血管的特征在于： 功能和结构异常，这会损害血管输送功能和心脏修复， MI.同样，异常的非生产性新血管形成代表了MI的有希望的治疗靶点 治疗在这里，通过利用内皮细胞谱系追踪和单细胞RNAseq技术，我们的初步 对鼠心肌梗死模型的研究揭示了通过内皮细胞介导的强大的内皮细胞（EC）可塑性， 间充质转化（Endo-MT，即，部分内皮间质转化） MI后修复。我们发现，内皮细胞获得间充质表型，包括高增殖和运动 心肌梗死后，导致血管异常和非生产性新血管形成。我们发现了一种PDGF/NF- kB/HIF-1a/Snail介导的控制Endo-MT的轴。值得注意的是，EC特异性缺失PDGF受体-b 促进小鼠心肌梗死后组织修复和心脏功能恢复。最后，药理学抑制 PDGF促进MI后心功能恢复。此外，Snail在人类MI相关的神经元中表达。 EC。基于这些发现，我们假设内皮可塑性驱动非生产性的 新血管形成并阻碍MI后的心脏修复。为了验证这一假设，我们将继续 以下目的：1）明确心肌梗死后内皮可塑性的分子机制; 2）确定 内皮可塑性在心肌梗死后异常新生血管形成和心脏修复中的体内作用; 3） 测试实验疗法，其靶向PDGFR介导的内皮可塑性用于MI治疗。因此， EC的可塑性可能为修复血管微环境和 改善MI后心脏修复和功能恢复。该项目的成功完成将提供新的 了解异常新生血管形成的机制，并可能导致新的 治疗缺血性心脏病的治疗收益。