Aberrant tumor blood vessels are prone to propel the malignant progression of tumors, and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor progression. Herein, we demonstrated that salvianic acid A (SAA) played a pivotal role in contributing to vascular normalization in the tumor-bearing mice, thereby improving delivery and effectiveness of the chemotherapeutic agent. SAA was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells (HUVECs) exposed to hypoxia. Mechanistically, SAA was inclined to directly bind to the glycolytic enzyme PKM2, leading to a dramatic decrease in endothelial glycolysis. More importantly, SAA improved the endothelial integrity activating the -Catenin/Claudin-5 signaling axis in a PKM2-dependent manner. Our findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.

中文翻译：

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用丹酚酸 A 靶向 PKM2 信号级联使肿瘤血管正常化以促进化疗药物输送

异常的肿瘤血管容易推动肿瘤的恶性进展，而针对肿瘤内皮细胞的异常代谢成为实现血管正常化和拮抗肿瘤进展的有希望的选择。在此，我们证明丹酚酸 A (SAA) 在促进荷瘤小鼠血管正常化方面发挥着关键作用，从而改善化疗药物的递送和有效性。 SAA 能够抑制糖酵解并增强暴露于缺氧的人脐静脉内皮细胞 (HUVEC) 中的内皮连接。从机制上讲，SAA 倾向于直接与糖酵解酶 PKM2 结合，导致内皮糖酵解急剧减少。更重要的是，SAA 改善了内皮完整性，以 PKM2 依赖性方式激活 -Catenin/Claudin-5 信号轴。我们的研究结果表明，SAA 可能作为诱导肿瘤血管正常化的有效药物。