CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands; Department of Physiology, Amsterdam University Medical Centers, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, the Netherlands.
Mol Ther. 2023 Jun 7;31(6):1807-1828. doi: 10.1016/j.ymthe.2023.04.007. Epub 2023 Apr 17.
While it is experimentally supported that impaired myocardial vascularization contributes to a mismatch between myocardial oxygen demand and supply, a mechanistic basis for disruption of coordinated tissue growth and angiogenesis in heart failure remains poorly understood. Silencing strategies that impair microRNA biogenesis have firmly implicated microRNAs in the regulation of angiogenesis, and individual microRNAs prove to be crucial in developmental or tumor angiogenesis. A high-throughput functional screening for the analysis of a whole-genome microRNA silencing library with regard to their phenotypic effect on endothelial cell proliferation as a key parameter, revealed several anti- and pro-proliferative microRNAs. Among those was miR-216a, a pro-angiogenic microRNA which is enriched in cardiac microvascular endothelial cells and reduced in expression under cardiac stress conditions. miR-216a null mice display dramatic cardiac phenotypes related to impaired myocardial vascularization and unbalanced autophagy and inflammation, supporting a model where microRNA regulation of microvascularization impacts the cardiac response to stress.
虽然实验证明心肌血管生成受损导致心肌氧需求与供应不匹配，但心力衰竭中协调的组织生长和血管生成破坏的机制基础仍知之甚少。沉默策略会损害 microRNA 的生物发生，这有力地表明 microRNA 参与了血管生成的调节，而且单个 microRNA 被证明在发育或肿瘤血管生成中至关重要。高通量功能筛选用于分析全基因组 microRNA 沉默文库，以研究其对内皮细胞增殖这一关键参数的表型影响，结果发现了几种抗增殖和促增殖的 microRNA。其中包括 miR-216a，它是一种促血管生成的 microRNA，在心脏微血管内皮细胞中丰富，并在心脏应激条件下表达减少。miR-216a 缺失小鼠表现出与心肌血管生成受损以及自噬和炎症失衡相关的明显心脏表型，支持这样一种模型，即 microRNA 对微血管生成的调节影响心脏对压力的反应。
