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Ca_v3.1 (_1G) controls von Willebrand factor secretion in rat pulmonary microvascular endothelial cells

¹Center for Lung Biology and Departments of ²Pharmacology, ³Physiology, and ⁴Cell Biology and Neuroscience, University of South Alabama College of Medicine, Mobile, Alabama; ⁵Department of Microbiology, Peking University Health Science Center, Beijing, China; ⁶Cancer Genomics Laboratory, University of South Alabama-Mitchell Cancer Institute, Mobile, Alabama; and ⁷Department of Plasma Proteins, Sanquin Research and Landsteiner Laboratory, Amsterdam, and Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

Submitted 22 September 2006 ; accepted in final form 12 December 2006

The T-type Ca²⁺ channel Ca_v3.1 subunit is present in pulmonary microvascular endothelial cells (PMVECs), but not in pulmonary artery endothelial cells (PAECs). The present study sought to assess the role of Ca_v3.1 in thrombin-induced Weibel-Palade body exocytosis and consequent von Willebrand factor (VWF) release. In PMVECs and PAECs transduced with a green fluorescent protein (GFP)-tagged VWF chimera, we examined the real-time dynamics and secretory process of VWF-GFP-containing vesicles in response to thrombin and the cAMP-elevating agent isoproterenol. Whereas thrombin stimulated a progressive decrease in the number of VWF-GFP-containing vesicles in both cell types, isoproterenol only decreased the number of VWF-GFP-containing vesicles in PAECs. In PMVECs, thrombin-induced decrease in the number of VWF-GFP-containing vesicles was nearly abolished by the T-type Ca²⁺ channel blocker mibefradil as well as by Ca_v3.1 gene silencing with small hairpin RNA. Expression of recombinant Ca_v3.1 subunit in PAECs resulted in pronounced increase in thrombin-stimulated Ca²⁺ entry, which is sensitive to mibefradil. Together, these data indicate that VWF secretion from lung endothelial cells is regulated by two distinct pathways involving Ca²⁺ or cAMP, and support the hypothesis that activation of Ca_v3.1 T-type Ca²⁺ channels in PMVECs provides a unique cytosolic Ca²⁺ source important for G_q-linked agonist-induced VWF release.

endothelial cells; thrombin

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