Endothelial dysfunction is an early event in coronary microvascular disease. Integrin-linked kinase (ILK) prevents endothelial nitric oxide synthase (eNOS) uncoupling and, thus, endothelial dysfunction. However, the specific role of endothelial ILK in cardiac function remains to be fully elucidated. We hypothesised that endothelial ILK plays a crucial role in maintaining coronary microvascular function and contractile performance in the heart. We generated an endothelial cell-specific ILK conditional knock-out mouse (ecILK cKO) and investigated cardiovascular function. Coronary endothelial ILK deletion significantly impaired cardiac function: ejection fraction, fractional shortening and cardiac output decreased, whilst left ventricle diastolic internal diameter decreased and E/A and E/Eʹ ratios increased, indicating not only systolic but also diastolic dysfunction. The functional data correlated with extensive extracellular matrix remodelling and perivascular fibrosis, indicative of adverse cardiac remodelling. Mice with endothelial ILK deletion suffered early ischaemic-like events with ST elevation and transient increases in cardiac troponins, which correlated with fibrotic remodelling. In addition, ecILK cKO mice exhibited many features of coronary microvascular disease: reduced cardiac perfusion, impaired coronary flow reserve and arterial remodelling with patent epicardial coronary arteries. Moreover, endothelial ILK deletion induced a moderate increase in blood pressure, but the antihypertensive drug Losartan did not affect microvascular remodelling whilst only partially ameliorated fibrotic remodelling. The plasma miRNA profile reveals endothelial-to-mesenchymal transition (endMT) as an upregulated pathway in endothelial ILK conditional KO mice. Our results show that endothelial cells in the microvasculature in endothelial ILK conditional KO mice underwent endMT. Moreover, endothelial cells isolated from these mice and ILK-silenced human microvascular endothelial cells underwent endMT, indicating that decreased endothelial ILK contributes directly to this endothelial phenotype shift. Our results identify ILK as a crucial regulator of microvascular endothelial homeostasis. Endothelial ILK prevents microvascular dysfunction and cardiac remodelling, contributing to the maintenance of the endothelial cell phenotype.

内皮功能障碍是冠状动脉微血管疾病的早期事件。整合素连接激酶 (ILK) 可防止内皮一氧化氮合酶 (eNOS) 解偶联，从而防止内皮功能障碍。然而，内皮ILK在心脏功能中的具体作用仍有待充分阐明。我们假设内皮ILK在维持冠状动脉微血管功能和心脏收缩性能方面发挥着至关重要的作用。我们构建了内皮细胞特异性 ILK 条件敲除小鼠 (ecILK cKO) 并研究了心血管功能。冠状动脉内皮ILK缺失显着损害心脏功能：射血分数、缩短分数和心输出量下降，同时左心室舒张内径减小，E/A和E/Eʹ比值增加，表明不仅收缩功能障碍，而且舒张功能障碍。功能数据与广泛的细胞外基质重塑和血管周围纤维化相关，表明不良心脏重塑。内皮细胞 ILK 缺失的小鼠会出现早期缺血样事件，伴有 ST 段抬高和心肌肌钙蛋白短暂增加，这与纤维化重塑相关。此外，ecILK cKO小鼠表现出冠状微血管疾病的许多特征：心脏灌注减少、冠状动脉血流储备受损以及心外膜冠状动脉开放的动脉重塑。此外，内皮细胞ILK缺失会导致血压适度升高，但抗高血压药物氯沙坦并不影响微血管重塑，而仅部分改善纤维化重塑。血浆 miRNA 谱揭示内皮间质转化 (endMT) 是内皮 ILK 条件 KO 小鼠中上调的途径。我们的结果表明，内皮 ILK 条件 KO 小鼠微血管系统中的内皮细胞接受了 endMT。此外，从这些小鼠中分离的内皮细胞和ILK沉默的人微血管内皮细胞进行了endMT，表明内皮ILK的减少直接导致了这种内皮表型转变。我们的结果表明 ILK 是微血管内皮稳态的重要调节因子。内皮 ILK 可预防微血管功能障碍和心脏重塑，有助于维持内皮细胞表型。