Published online before print July 17, 2003, doi: 10.1161/01.RES.0000087148.75363.8F
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Submitted on May 28, 2003
Revised on July 9, 2003
Accepted on July 9, 2003
Cav3.1 (
1G) T-Type Ca2+ Channels Mediate Vaso-Occlusion of Sickled Erythrocytes in Lung Microcirculation
Songwei Wu *;
From the Departments of Pharmacology (S.W., T.S.), Medicine (J.H.), and Pathology (J.R.S.), the Center for Lung Biology (S.W., J.H., T.S.), and the Comprehensive Sickle Cell Center (J.H., B.O.O.), University of South Alabama College of Medicine, Mobile, Ala, and the Department of Pharmacology (J.T.T., M.L.), Tulane University School of Medicine, New Orleans, La.
* To whom correspondence should be addressed. E-mail: swu{at}jaguar1.usouthal.edu.
In the present study, we demonstrate that lung microvascular endothelial cells express a Cav3.1 (
1G) T-type voltage-gated Ca2+ channel, whereas lung macrovascular endothelial cells do not express voltage-gated Ca2+ channels. Voltage-dependent activation indicates that the Cav3.1 T-type Ca2+ current is shifted to a positive potential, at which maximum current activation is -10 mV; voltage-dependent conductance and inactivation properties suggest a "window current" in the range of -60 to -30 mV. Thrombin-induced membrane depolarization activates the Cav3.1 channel, resulting in a physiologically relevant cytosolic Ca2+ transition. Furthermore, activation of the Cav3.1 channel induces a procoagulant endothelial phenotype; eg, channel inhibition attenuates increased retention of sickled erythrocytes in the inflamed pulmonary circulation. We conclude that activation of the Cav3.1 channels selectively induces phenotypic changes in microvascular endothelial cells that mediate vaso-occlusion by sickled erythrocytes in the inflamed lung microcirculation.
Key words: endothelial cells • store-operated Ca2+ entry • P-selectin • von Willebrand factor • coagulation
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