Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II-dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II-treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.

中文翻译：

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Plk1 调节有丝分裂后平滑肌细胞的收缩，是血管稳态所必需的。


Polo 样激酶 1 (PLK1) 是细胞分裂的重要调节因子，目前正在作为癌症治疗靶点进行临床评估。我们报告了 Plk1 在维持心血管稳态方面的意外功能。小鼠中 Plk1 单倍体不足并不会引起明显的细胞增殖缺陷，但会导致动脉结构改变，从而经常导致主动脉破裂和死亡。血管平滑肌细胞 (VSMC) 中 Plk1 的特异性消融导致动脉弹性降低、低血压以及体内动脉对血管紧张素 II 的反应受损。从机制上讲，我们发现 Plk1 以不依赖有丝分裂的方式调节 VSMC 中 RhoA 和肌动球蛋白动力学的血管紧张素 II 依赖性激活。这种调节取决于 Plk1 激酶活性，对血管紧张素 II 治疗的小鼠施用小分子 Plk1 抑制剂会导致动脉健康度降低，动脉瘤和主动脉破裂的风险增加。因此，我们得出结论，部分降低 Plk1 活性不会阻止细胞分裂，但仍会损害主动脉稳态。我们的研究结果对当前旨在抑制 PLK1 癌症治疗的方法具有潜在的重要意义。