Glycolytic regulation of cell rearrangement in angiogenesis.
Glycolytic regulation of cell rearrangement in angiogenesis.
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DOI：
10.1038/ncomms12240
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发表时间：
2016-07-20
影响因子：
16.6
通讯作者：
Carmeliet P
中科院分区：
文献类型：
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作者：
Cruys B;Wong BW;Kuchnio A;Verdegem D;Cantelmo AR;Conradi LC;Vandekeere S;Bouché A;Cornelissen I;Vinckier S;Merks RM;Dejana E;Gerhardt H;Dewerchin M;Bentley K;Carmeliet P
在血管出芽过程中，内皮细胞（ECs）在芽体中动态地重新排列位置以竞争顶端位置。我们最近发现糖酵解激活剂PFKFB3通过调节细胞骨架重塑、迁移和顶端细胞竞争力，在血管出芽中起关键作用。然而，糖酵解如何在血管出芽过程中调节内皮细胞重排尚不清楚。在此我们报道，经实验验证的计算机模拟预测，ATP的糖酵解产物通过促进丝状伪足形成和降低细胞间黏附来驱动内皮细胞重排。值得注意的是，模拟正确地预测了阻断PFKFB3可使高血管内皮生长因子（VEGF）条件下紊乱的内皮细胞重排正常化，正如在病理性血管生成过程中发生的那样。这项跨学科研究将内皮细胞代谢整合到血管出芽中，对糖酵解控制血管出芽产生了机制上的见解，并为癌症和非恶性疾病中的血管正常化提出了抗糖酵解疗法。
糖酵解调节剂PFKFB3是血管出芽的关键因素。在此作者开发了一个计算机模型，预测PFKFB3通过促进丝状伪足形成和降低细胞间黏附来驱动血管出芽过程中的内皮细胞重排，并通过实验验证了这一预测。
During vessel sprouting, endothelial cells (ECs) dynamically rearrange positions in the sprout to compete for the tip position. We recently identified a key role for the glycolytic activator PFKFB3 in vessel sprouting by regulating cytoskeleton remodelling, migration and tip cell competitiveness. It is, however, unknown how glycolysis regulates EC rearrangement during vessel sprouting. Here we report that computational simulations, validated by experimentation, predict that glycolytic production of ATP drives EC rearrangement by promoting filopodia formation and reducing intercellular adhesion. Notably, the simulations correctly predicted that blocking PFKFB3 normalizes the disturbed EC rearrangement in high VEGF conditions, as occurs during pathological angiogenesis. This interdisciplinary study integrates EC metabolism in vessel sprouting, yielding mechanistic insight in the control of vessel sprouting by glycolysis, and suggesting anti-glycolytic therapy for vessel normalization in cancer and non-malignant diseases. Glycolytic regulator PFKFB3 is a key player in vessel sprouting. Here the authors develop a computational model predicting that PFKFB3 drives endothelial cell rearrangement during vessel sprouting by promoting filopodia formation and reducing intercellular adhesion, and empirically validate this prediction.