Microtubule‐depolymerizing agents can selectively disrupt tumor vessels via inducing endothelial membrane blebbing. However, the mechanism regulating blebbing is largely unknown. IMB5046 is a newly discovered microtubule‐depolymerizing agent. Here, the functions of focal adhesion kinase (FAK) during IMB5046‐induced blebbing and the relevant mechanism are studied. We found that IMB5046 induced membrane blebbing and reassembly of focal adhesions in human vascular endothelial cells. Both FAK inhibitor and knock‐down expression of FAK inhibited IMB5046‐induced blebbing. Mechanism study revealed that IMB5046 induced the activation of FAK via GEF‐H1/ Rho/ ROCK/ MLC2 pathway. cRGD peptide, a ligand of integrin, also blocked IMB5046‐induced blebbing. After activation, FAK further promoted the phosphorylation of MLC2. This positive feedback loop caused more intensive actomyosin contraction and continuous membrane blebbing. FAK inhibitor blocked membrane blebbing via inhibiting actomyosin contraction, and stimulated stress fibre formation via promoting the phosphorylation of HSP27. Conclusively, these results demonstrate that FAK is a molecular switch controlling endothelial blebbing and stress fibre formation. Our study provides a new molecular mechanism for microtubule‐depolymerizing agents to be used as vascular disrupting agents.

中文翻译：

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黏着斑激酶由微管解聚剂激活，并调节人内皮细胞的膜起泡。

微管解聚剂可以通过诱导内皮膜起泡来选择性破坏肿瘤血管。然而，调节起泡的机制在很大程度上是未知的。IMB5046是新发现的微管解聚剂。在此，研究了IMB5046引起的起搏过程中粘着斑激酶（FAK）的功能及其相关机制。我们发现IMB5046诱导人血管内皮细胞中膜起泡和粘着斑的重组。FAK抑制剂和FAK的敲低表达均抑制IMB5046引起的起泡。机制研究表明，IMB5046通过GEF-H1 / Rho / ROCK / MLC2途径诱导FAK活化。整合素的配体cRGD肽也阻断了IMB5046引起的起泡。活化后，FAK进一步促进了MLC2的磷酸化。这种积极的反馈回路导致更强烈的肌动球蛋白收缩和连续的膜起泡。FAK抑制剂通过抑制肌动球蛋白收缩来阻止膜起泡，并通过促进HSP27的磷酸化来刺激应激纤维的形成。结论是，这些结果表明FAK是控制内皮起泡和应力纤维形成的分子开关。我们的研究为微管解聚剂用作血管破坏剂提供了新的分子机制。这些结果证明FAK是控制内皮起泡和应力纤维形成的分子开关。我们的研究为微管解聚剂用作血管破坏剂提供了新的分子机制。这些结果证明FAK是控制内皮起泡和应力纤维形成的分子开关。我们的研究为微管解聚剂用作血管破坏剂提供了新的分子机制。