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Myosin IIa is critical for cAMP-mediated endothelial secretion of von Willebrand factor

Pin Li, Guoqin Wei, Yang Cao, Qiuping Deng, Xiaofan Han, Xiaoshuai Huang, Yingqing Huo, Yulong He, Liangyi Chen and Jincai Luo

Key points

  • Myosin IIa is required for cAMP-mediated endothelial VWF secretion critical for hemostasis and thrombosis.

  • Myosin IIa regulates mature WPB positioning and facilitates WPB exocytosis via zyxin-mediated actin framework formation before fusion.

Abstract

Non-muscle 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 cAMP-mediated endothelial VWF secretion. Down-regulation 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; upon stimulation by cAMP agonists, myosin IIa in synergy with zyxin promotes the formation of functional actin framework, which is derived from pre-existing 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 pre-existing cortical actin filaments and exocytosing vesicles before fusion, but also reveal myosin IIa as a physiological regulator of endothelial VWF secretion in stress-induced hemostasis and thrombosis.

  • Submitted August 16, 2017.
  • Accepted November 14, 2017.