Endothelial exocytosis of Weibel–Palade body (WPB) is one of the first lines of defence against vascular injury. However, the mechanisms that control WPB exocytosis in the final stages (including the docking, priming and fusion of granules) are poorly understood. Here we show that the focal adhesion protein zyxin is crucial in this process. Zyxin downregulation inhibits the secretion of von Willebrand factor (VWF), the most abundant cargo in WPBs, from human primary endothelial cells (ECs) induced by cAMP agonists. Zyxin-deficient mice exhibit impaired epinephrine-stimulated VWF release, prolonged bleeding time and thrombosis, largely due to defective endothelial secretion of VWF. Using live-cell super-resolution microscopy, we visualize previously unappreciated reorganization of pre-existing actin filaments around WPBs before fusion, dependent on zyxin and an interaction with the actin crosslinker α-actinin. Our findings identify zyxin as a physiological regulator of endothelial exocytosis through reorganizing local actin network in the final stage of exocytosis.

Purpose -Strategic concentration is a key issue for manufacturing companies when designing a supply chain. As a corporate strategy and a supply chain governance strategy, vertical integration relates to organisational economics and strategic supply chain management. Numerous explanations have been created for vertical integration, and transaction cost economics (TCE) provides a theoretical basis to help understand the process. However, the current popularity of vertical integration seems inspired by something more than altering industry structure and minimising cost, which are the traditionally accepted explanations for vertical integration This paper aims to explore the driving forces for vertical integration, particularly downstream integration of distribution, and the consequences of vertical integration in a manufacturer-distributor-reseller chain. Design/methodology/approach -This study adopted an exploratory case study approach to examine a Swedish-based timber manufacturer that vertically integrated a distribution centre in the UK, which made it a direct supplier to DIY retailers and builders' merchants. Data were collected primarily through open-ended, face-to-face interviews. Findings -The study found that the most important factors driving the manufacturer's vertical integration of distribution were the demands of large retail chains and the manufacturer's decisions to focus on developing its positioning strategy in the supply chain. Vertical integration has transformed the manufacturer into a supplier to large timber products resellers, offering the firm a greater potential to provide integrated solutions and, therefore, become a strategic partner to its customers. Originality/value -This empirical study examined a building material distribution channel, a subject that has rarely been studied. Study results add empirical evidence to explanations and impacts of vertical integration, especially the integration of customer interface.

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 reveal myosin IIa as a physiological regulator of endothelial VWF secretion in stress-induced hemostasis and thrombosis.

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