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Blood, 1 April 2006, Vol. 107, No. 7, pp. 2736-2744. Prepublished online as a Blood First Edition Paper on December 6, 2005; DOI 10.1182/blood-2004-07-2698. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-07-2698v1 107/7/2736    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cleator, J. H. Articles by Hamm, H. E. Search for Related Content PubMed PubMed Citation Articles by Cleator, J. H. Articles by Hamm, H. E. Related Collections Hemostasis, Thrombosis, and Vascular Biology Cell Adhesion and Motility Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP John H. Cleator, Wen Qin Zhu, Douglas E. Vaughan, and Heidi E. Hamm From the Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN; and the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN. Thrombin-mediated endothelial-cell release of von Willebrand factor (VWF) and P-selectin functionally links protease-activated receptors (PARs) to thrombosis and inflammation. VWF release can be stimulated by both Ca2+ and cAMP, and, although both VWF and P-selectin are found in Weibel-Palade bodies (WPBs), we found that their release could be differentially regulated. In these studies, human umbilical vein endothelial cells stimulated with cAMP or PAR2-AP led to a delayed release of VWF and significantly less P-selectin release compared with histamine, thrombin, or PAR1-AP. Dose-response studies revealed that PAR2-AP was significantly less efficacious in promoting the release of P-selectin compared with VWF. PAR2-AP–induced robust stimulation of intracellular Ca2+ coupled with a significantly greater inhibitory effect of calcium chelation on release of VWF compared with cell-surface expression of P-selectin, suggests an additional Ca2+-independent pathway involved in release of P-selectin. PAR2-AP failed to increase global cAMP levels; however, inhibition of protein kinase A led to a significant attenuation of PAR2-AP–mediated release of VWF. Confocal microscopy studies revealed that PAR2 and forskolin caused preferential release of a population of Weibel-Palade bodies (WPBs) consisting of only VWF. Thus, WPBs are pharmacologically and morphologically heterogeneous, and distinct granule populations are susceptible to differential regulation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. I. Borissoff, H. M.H. Spronk, S. Heeneman, and H. ten Cate Is thrombin a key player in the 'coagulation-atherogenesis' maze? Cardiovasc Res, June 1, 2009; 82(3): 392 - 403. [Abstract] [Full Text] [PDF] J. H. Cleator and D. E. Vaughan Clinical Implications of the Contrasting Effects of In Vivo Thrombin Receptor Activation (Protease-Activated Receptor Type 1) on the Human Vasculature J. Am. Coll. Cardiol., May 6, 2008; 51(18): 1757 - 1759. [Full Text] [PDF] J. E. Italiano Jr, J. L. Richardson, S. Patel-Hett, E. Battinelli, A. Zaslavsky, S. Short, S. 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Wu Cav3.1 ({alpha}1G) controls von Willebrand factor secretion in rat pulmonary microvascular endothelial cells Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L833 - L844. [Abstract] [Full Text] [PDF] I. J. Gudmundsdottir, I. L. Megson, J. S. Kell, C. A. Ludlam, K. A.A. Fox, D. J. Webb, and D. E. Newby Direct Vascular Effects of Protease-Activated Receptor Type 1 Agonism In Vivo in Humans Circulation, October 10, 2006; 114(15): 1625 - 1632. [Abstract] [Full Text] [PDF] S. Amadesi, G. S. Cottrell, L. Divino, K. Chapman, E. F. Grady, F. Bautista, R. Karanjia, C. Barajas-Lopez, S. Vanner, N. Vergnolle, et al. Protease-activated receptor 2 sensitizes TRPV1 by protein kinase C{varepsilon}- and A-dependent mechanisms in rats and mice J. Physiol., September 1, 2006; 575(2): 555 - 571. [Abstract] [Full Text] [PDF]

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