Myosin IIa is critical for cAMP-mediated endothelial secretion of von Willebrand factor
Myosin IIa is critical for cAMP-mediated endothelial secretion of von Willebrand factor
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肌球蛋白 IIa 对于 cAMP 介导的血管性血友病因子的内皮分泌至关重要
DOI：
10.1182/blood-2017-08-802140
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发表时间：
2018-02-08
期刊：
影响因子：
20.3
通讯作者：
Luo, Jincai
中科院分区：
文献类型：
--
作者：
Li, Pin;Wei, Guoqin;Luo, Jincai
非肌肉肌球蛋白 II 与内皮 Weibel-Palade 小体 (WPB) 释放血管性血友病因子 (VWF) 的调节有关，但肌球蛋白 IIa 亚型的具体作用尚不清楚。在这里，我们报告肌球蛋白 IIa 在原代人内皮细胞和完整小鼠血管中表达，对于环磷酸腺苷 (cAMP) 介导的内皮 VWF 分泌至关重要。 shRNA 下调肌球蛋白 IIa 显着抑制毛喉素和肾上腺素诱导的 VWF 分泌。内皮特异性肌球蛋白 IIa 敲除小鼠表现出肾上腺素刺激的 VWF 释放受损、出血时间延长和血栓形成。进一步的研究表明，在静息细胞中，肌球蛋白 IIa 缺乏破坏了 Rab27 阳性 WPB 沿应力纤维的外周定位；在 cAMP 激动剂的刺激下，肌球蛋白 IIa 与 zyxin 协同促进功能性肌动蛋白框架的形成，该框架源自 WPB 周围预先存在的皮质肌动蛋白丝，促进融合和随后的胞吐作用。总之，我们的研究结果不仅确定了肌球蛋白 IIa 在调节 WPB 定位以及融合前预先存在的皮质肌动蛋白丝和胞吐囊泡之间的相互作用中的新功能，而且还揭示了肌球蛋白 IIa 在应激诱导的止血和血栓形成中作为内皮 VWF 分泌的生理调节剂。
Nonmuscle myosin II has been implicated in regulation of von Willebrand factor (VWF) release from endothelial Weibel-Palade bodies (WPBs), but the specific role of myosin IIa isoform is poorly defined. Here, we report that myosin IIa is expressed both in primary human endothelial cells and intact mouse vessels, essential for cyclic adenosine monophosphate (cAMP)-mediated endothelial VWF secretion. Downregulation of myosin IIa by shRNAs significantly suppressed both forskolin-and epinephrine-induced VWF secretion. Endothelium-specific myosin IIa knockout mice exhibited impaired epinephrine-stimulated VWF release, prolonged bleeding time, and thrombosis. Further study showed that in resting cells, myosin IIa deficiency disrupted the peripheral localization of Rab27-positive WPBs along stress fibers; on stimulation by cAMP agonists, myosin IIa in synergy with zyxin promotes the formation of a functional actin framework, which is derived from preexisting cortical actin filaments, around WPBs, facilitating fusion and subsequent exocytosis. In summary, our findings not only identify new functions of myosin IIa in regulation of WPB positioning and the interaction between preexisting cortical actin filaments and exocytosing vesicles before fusion but also revealmyosin IIa as a physiological regulator of endothelial VWF secretion in stress-induced hemostasis and thrombosis.