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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.
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Submitted July 21, 2004
Accepted November 17, 2005
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*
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA; Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA
Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
* Corresponding author; email: heidi.hamm{at}vanderbilt.edu.
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 to histamine, thrombin or PAR1-AP. Dose response studies revealed that PAR2-AP was significantly less efficacious in promoting the release of P-selectin compared to VWF. PAR2-AP-induced robust stimulation of intracellular Ca2+ coupled with a significantly greater inhibitory effect of calcium chelation on release of VWF compared to 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 WPBs consisting of only VWF. Thus, WPBs are pharmacologically and morphologically heterogeneous and distinct granule populations are susceptible to differential regulation.
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