Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
Cardiovasc Res. 2021 Apr 23;117(5):1257-1273. doi: 10.1093/cvr/cvaa287.
Acute myocardial infarction (MI) inflicts massive injury to the coronary microcirculation leading to vascular disintegration and capillary rarefication in the infarct region. Tissue repair after MI involves a robust angiogenic response that commences in the infarct border zone and extends into the necrotic infarct core. Technological advances in several areas have provided novel mechanistic understanding of postinfarction angiogenesis and how it may be targeted to improve heart function after MI. Cell lineage tracing studies indicate that new capillary structures arise by sprouting angiogenesis from pre-existing endothelial cells (ECs) in the infarct border zone with no meaningful contribution from non-EC sources. Single-cell RNA sequencing shows that ECs in infarcted hearts may be grouped into clusters with distinct gene expression signatures, likely reflecting functionally distinct cell populations. EC-specific multicolour lineage tracing reveals that EC subsets clonally expand after MI. Expanding EC clones may arise from tissue-resident ECs with stem cell characteristics that have been identified in multiple organs including the heart. Tissue repair after MI involves interactions among multiple cell types which occur, to a large extent, through secreted proteins and their cognate receptors. While we are only beginning to understand the full complexity of this intercellular communication, macrophage and fibroblast populations have emerged as major drivers of the angiogenic response after MI. Animal data support the view that the endogenous angiogenic response after MI can be boosted to reduce scarring and adverse left ventricular remodelling. The improved mechanistic understanding of infarct angiogenesis therefore creates multiple therapeutic opportunities. During preclinical development, all proangiogenic strategies should be tested in animal models that replicate both cardiovascular risk factor(s) and the pharmacotherapy typically prescribed to patients with acute MI. Considering that the majority of patients nowadays do well after MI, clinical translation will require careful selection of patients in need of proangiogenic therapies.
急性心肌梗死（MI）会对冠状动脉微循环造成严重损伤，导致梗死区域的血管解体和毛细血管稀疏。MI 后的组织修复涉及到强大的血管生成反应，该反应始于梗死边缘区，并延伸到坏死的梗死核心区。多个领域的技术进步为梗死后血管生成提供了新的机制理解，以及如何针对其来改善 MI 后心脏功能。细胞谱系追踪研究表明，新的毛细血管结构通过梗死边缘区的出芽血管生成从预先存在的内皮细胞（EC）中产生，而非 EC 来源没有显著贡献。单细胞 RNA 测序表明，梗死心脏中的 EC 可根据其独特的基因表达特征分为不同的簇，可能反映了具有不同功能的细胞群体。EC 特异性多色谱系追踪显示，MI 后 EC 亚群克隆性扩增。扩张的 EC 克隆可能来自具有干细胞特征的组织驻留 EC，这些细胞已在包括心脏在内的多个器官中被鉴定出来。MI 后的组织修复涉及多种细胞类型之间的相互作用，这些相互作用在很大程度上是通过分泌蛋白及其同源受体进行的。虽然我们才刚刚开始理解这种细胞间通讯的全部复杂性，但巨噬细胞和成纤维细胞群体已成为 MI 后血管生成反应的主要驱动因素。动物数据支持这样的观点，即 MI 后内源性血管生成反应可以被增强以减少瘢痕形成和不良的左心室重构。因此，对梗死血管生成的更深入理解为治疗提供了多种机会。在临床前开发过程中，所有促血管生成策略都应在动物模型中进行测试，这些模型复制了心血管危险因素和通常开给急性 MI 患者的药物治疗。考虑到现在大多数患者在 MI 后状况良好，临床转化将需要仔细选择需要血管生成治疗的患者。
