However, Metformin order in 1957 [3] we suggested that the gene was autosomal dominant, which was confirmed by the pattern found by Zhang et al. in 1992 [13,14]. Weibel-Palade bodies

(WPB) are endothelial cell specific elongated secretory organelles that contain von Willebrand factor (VWF) and a variety of other proteins, including tissue-type plasminogen activator (tPA), P-selectin, interleukin-8 (IL-8) and angiopoietin-2. These mediators, which can be released from vascular endothelial cells upon stimulation of the cells by signalling molecules or mechanical stress, contribute to inflammation, angiogenesis and tissue repair (for an extensive review on WPBs see [15]). These organelles with a diameter of 0.1–0.3 μm and a length of 1–5 μm were first described in 1964 by Ewald Weibel and George Palade [16]. VWF is the major constituent of WPBs and is a prerequisite for

the biogenesis of WPBs: endothelial cells of VWF-deficient animals lack WPB, whereas other non-endothelial find more cell types will form WPB-like organelles upon expression of recombinant VWF. During posttranslational modifications in the trans-Golgi network, VWF multimers are formed and are subsequently condensed into tubules that are targeted to WPBs [15,17]. Those tubules can be recognized by electron microscopy as the characteristic longitudinal striations in the WPB. Many secretagogues mediate release of WPBs, either by increasing intracellular free calcium (thrombin and histamine) or cAMP (epinephrine and vasopressin). Upon exocytosis, the VWF tubules unfurl into VWF strings that dock on the endothelial cells to mediate platelet adhesion.

Three different modes of regulated exocytosis of WPBs have been described [15]: conventional exocytosis, in which single WPBs fuse with the plasma membrane and release their content; lingering-kiss exocytosis, where single WPBs fuse transiently with the plasma membrane via a small fusion pore and selectively release small molecules only but retain VWF [18]; and multigranular exocytosis, where several WPBs coalesce before exocytosis into large vesicles termed secretory pods [19]. When VWF is released into the blood it can form long strings and networks of strings that remain associated with the Urease cells for some time and provide a platform for platelet adhesion. How the strings anchor to the plasma membrane is still a matter of debate, but integrin αvβ3 and P-selectin are potential candidates. Weibel-Palade bodies play a crucial role in the storage and timely secretion of VWF and defects in these processes may contribute to the phenotype of patients with von Willebrand’s disease (VWD). The regulated secretion of VWF from WPBs can be stimulated with the synthetic vasopressin analogue 1-8 deamino-D-arginine vasopressin (DDAVP). DDAVP induces a prompt two to fourfold increase in VWF plasma concentration and is therefore an important treatment modality in patients with VWD.