Endothelial plasticity in cardiac repair after myocardial infarction

项目摘要 在西方世界，缺血性心脏病是最常见的死亡原因，主要由心肌梗塞引起。 心肌梗死(MI)是冠状动脉内血管闭塞对心肌组织造成的不可逆性损伤 动脉。心肌梗死后，新血管的形成，即新生血管，对缺血组织至关重要 再灌流和修复。然而，梗死组织中新形成的血管具有以下特征 功能和结构异常，影响血管输送功能和心脏修复 密西西比。同样，异常的非生产性新生血管是心肌梗塞的一个有希望的治疗靶点。 治疗。在这里，通过利用内皮谱系追踪和单细胞RNAseq技术，我们的初步 小鼠心肌梗死模型研究显示内皮细胞(EC)通过内皮细胞介导的强大可塑性 心脏间质转化(Endo-MT，即部分内皮间充质转化) 心肌梗死后修复。我们发现内皮细胞获得了包括高增殖和高运动性在内的间质表型。 心肌梗死后，导致血管异常和非生产性新生血管。我们确定了一个PDGF/NF- Kb/HIF-1a/Snail介导轴控制Endo-MT。值得注意的是，EC特异性的PDGF受体-b的缺失 促进小鼠心肌梗死后组织修复和心功能恢复。最后，对药物的抑制作用 PDGF可促进心肌梗死后心功能恢复。此外，Snail在人类心肌梗死相关基因中也有表达 ECS。基于这些发现，我们假设内皮细胞的可塑性推动了非生产性 心肌梗死后新生血管并阻碍心脏修复。为了检验这一假设，我们将继续 目的：1)明确心肌梗死后内皮细胞可塑性的分子机制；2)确定心肌梗死后内皮细胞的可塑性 内皮可塑性在心肌梗死后异常新生血管和心脏修复中的作用；3) 针对心肌梗死治疗的以PDGFR介导的内皮可塑性为靶点的实验治疗。因此，目标是 血管内皮细胞的可塑性可能为修复血管微环境提供一个有前途的治疗机会。 促进心肌梗死后心脏修复和功能恢复。该项目的成功完成将提供新的 对异常新生血管机制的洞察并可能导致新的 治疗缺血性心脏病的治疗收入。

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.