Endothelial KIT Signalling After Myocardial Infarction

心肌梗塞后的内皮 KIT 信号转导

• 批准号: 530210503
• 负责人: Professor Dr. Kai Christoph Wollert
• 金额: --
• 依托单位: Klinik für Kardiologie und Angiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/530210503?language=en
• 关键词: Endothelial; KIT; Signalling; After; Myocardial

Acute myocardial infarction (MI) inflicts massive injury to the coronary microcirculation leading to vascular disintegration and capillary rarefication. Within days, a new vascular plexus develops in the infarct region, helping to limit the extent of scarring and left ventricular remodelling. Paracrine-acting growth factors play a central role in the regulation of angiogenesis after MI. In the previous project, we identified the monocyte- and macrophage-derived cytokine meteorin-like (METRNL) as a new angiogenic growth factor and high-affinity ligand for the endothelial KIT receptor. We found that both KIT(+) and KIT(-) endothelial cells (ECs) contribute to the capillarisation of the infarct region. In Metrnl-deficient mice, the expansion of KIT(+) ECs in the infarct region was selectively abolished and the animals developed severe heart failure. Our single-cell RNA sequencing (scRNA-seq) analyses identify KIT(+) ECs as a highly activated cell population after MI. We conclude that KIT labels an EC population that is crucial for proper wound healing. We postulate that KIT, along with a putative co-receptor (see below), induces the expansion and activation of this EC population. Both hypotheses shall be investigated in our project. In order to directly analyse the importance of the endothelial KIT receptor for angiogenesis and wound healing after MI, we have generated Kitfl/fl mice to selectively delete Kit in ECs before MI. Furthermore, we are planning sequential scRNA-seq analyses in Metrnl-deficient and EC-selective Kit-deficient mice to characterise the influence of METRNL and KIT on the composition of the EC compartment and to identify METRNL and KIT-activated target genes after MI. We are particularly interested in whether METRNL and KIT also influence infarct healing via angiocrine growth factors. Recent observations from our group indicate that not all KIT-expressing cell types are responsive to METRNL and suggest that there is a co-receptor rendering KIT(+) ECs METRNL-responsive. Indeed, in a bioinformatic analysis, we have discovered a co-receptor candidate in KIT(+) ECs that appears to be required, alongside KIT, for METRNL-mediated angiogenetic effects. We want to understand the putative interaction of METRNL and/or KIT with this co-receptor at the molecular level and to investigate the co-receptor’s importance for angiogenesis and wound healing after MI in a loss-of-function mouse model. Our investigations will enable a better understanding of cardiac EC heterogeneity and its importance for vascular repair after MI.

急性心肌梗死（MI）对冠状动脉微循环造成严重损伤，导致血管崩解和毛细血管稀疏。几天之内，一个新的血管丛在梗死区域形成，有助于限制瘢痕形成和左心室重塑的程度。旁分泌作用生长因子在心肌梗死后血管生成的调节中起重要作用。在以前的项目中，我们确定了单核细胞和巨噬细胞衍生的细胞因子类流星蛋白（METRNL）作为一种新的血管生成生长因子和内皮KIT受体的高亲和力配体。我们发现KIT（+）和KIT（-）内皮细胞（EC）都有助于梗死区域的毛细血管化。在Metrnl缺陷小鼠中，梗死区域KIT（+）EC的扩增被选择性消除，动物发生严重的心力衰竭。我们的单细胞RNA测序（scRNA-seq）分析将KIT（+）EC鉴定为MI后高度活化的细胞群。我们的结论是，KIT标记的EC人口是至关重要的适当的伤口愈合。我们假设KIT，沿着一个假定的共受体（见下文），诱导该EC群体的扩增和活化。这两个假设都将在我们的项目中进行研究。为了直接分析内皮KIT受体对MI后血管生成和伤口愈合的重要性，我们产生了Kitfl/fl小鼠以在MI前选择性地删除EC中的Kit。此外，我们计划在Metrnl缺陷和EC选择性Kit缺陷小鼠中进行连续scRNA-seq分析，以确定METRNL和KIT对EC隔室组成的影响，并在MI后鉴定METRNL和KIT激活的靶基因。我们特别感兴趣的是METRNL和KIT是否也通过血管分泌生长因子影响梗死愈合。我们小组最近的观察表明，并非所有表达KIT的细胞类型都对METRNL有反应，并表明存在使KIT（+）EC对METRNL有反应的共受体。事实上，在生物信息学分析中，我们已经发现了KIT（+）EC中的一种辅助受体候选物，该候选物似乎与KIT一起是METRNL介导的血管生成效应所需的。我们希望了解METRNL和/或KIT与该辅助受体在分子水平上的假定相互作用，并在功能丧失小鼠模型中研究辅助受体对MI后血管生成和伤口愈合的重要性。我们的研究将使更好地了解心脏EC异质性及其对MI后血管修复的重要性。