King's College London British Heart Foundation Centre, School of Cardiovascular & Metabolic Medicine and Sciences, London, UK.
The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
Nat Commun. 2023 Sep 9;14(1):5552. doi: 10.1038/s41467-023-41326-2.
The microvasculature plays a key role in tissue perfusion and exchange of gases and metabolites. In this study we use human blood vessel organoids (BVOs) as a model of the microvasculature. BVOs fully recapitulate key features of the human microvasculature, including the reliance of mature endothelial cells on glycolytic metabolism, as concluded from metabolic flux assays and mass spectrometry-based metabolomics using stable tracing of C-glucose. Pharmacological targeting of PFKFB3, an activator of glycolysis, using two chemical inhibitors results in rapid BVO restructuring, vessel regression with reduced pericyte coverage. PFKFB3 mutant BVOs also display similar structural remodelling. Proteomic analysis of the BVO secretome reveal remodelling of the extracellular matrix and differential expression of paracrine mediators such as CTGF. Treatment with recombinant CTGF recovers microvessel structure. In this work we demonstrate that BVOs rapidly undergo restructuring in response to metabolic changes and identify CTGF as a critical paracrine regulator of microvascular integrity.
微血管在组织灌注和气体及代谢物交换中起着关键作用。在这项研究中，我们使用人类血管类器官（BVOs）作为微血管模型。BVOs 充分再现了人类微血管的关键特征，包括成熟内皮细胞对糖酵解代谢的依赖，这是通过代谢通量分析和基于稳定 C-葡萄糖追踪的基于质谱的代谢组学得出的结论。使用两种化学抑制剂对糖酵解激活剂 PFKFB3 的药理学靶向作用导致 BVO 快速重构，血管收缩，周细胞覆盖减少。PFKFB3 突变体 BVOs 也显示出类似的结构重塑。BVOs 分泌组的蛋白质组学分析揭示了细胞外基质的重塑和旁分泌介质如 CTGF 的差异表达。用重组 CTGF 处理可恢复微血管结构。在这项工作中，我们证明了 BVOs 会迅速响应代谢变化进行结构重构，并确定 CTGF 是微血管完整性的关键旁分泌调节剂。
