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(Circulation Research. 2005;96:856.)
© 2005 American Heart Association, Inc.

Cellular Biology

Essential Role of a Ca²⁺-Selective, Store-Operated Current (I_SOC) in Endothelial Cell Permeability

Determinants of the Vascular Leak Site

Songwei Wu, Eugene A. Cioffi, Diego Alvarez, Sarah L. Sayner, Hairu Chen, Donna L. Cioffi, Judy King, Judy R. Creighton, Mary Townsley, Steven R. Goodman, Troy Stevens

From the Center for Lung Biology (S.W., D.A., S.L.S., H.C., D.L.C., J.K., J.R.C., M.T., T.S.) and Departments of Chemistry (E.A.C.), Pathology (J.K.), Pharmacology (S.W., S.L.S., D.L.C., T.S.), and Physiology (D.A., M.T.), The University of South Alabama College of Medicine, Mobile, Ala; and the Department of Cell Biology (S.R.G.), The University of Texas at Dallas, Dallas, Tex.

Correspondence to Troy Stevens, PhD, Professor, Department of Molecular and Cellular Pharmacology, Director, Center for Lung Biology, MSB 3364, University of South Alabama College of Medicine, Mobile, AL 36688. E-mail tstevens{at}jaguar1.usouthal.edu

Store-operated calcium (SOC) entry is sufficient to disrupt the extra-alveolar, but not the alveolar, endothelial cell barrier. Mechanism(s) underlying such insensitivity to transitions in cytosolic calcium ([Ca²⁺]_i) in microvascular endothelial cells are unknown. Depletion of stored Ca²⁺ activates a larger SOC entry response in extra-alveolar (pulmonary artery; PAECs) than alveolar (pulmonary microvascular; PMVECs) endothelial cells. In vivo permeation studies revealed that Ca²⁺ store depletion activates similar nonselective cationic conductances in PAECs and PMVECs, while only PAECs possess the calcium-selective, store-operated Ca²⁺ entry current, I_SOC. Pretreatment with the type 4 phosphodiesterase inhibitor, rolipram, abolished thapsigargin-activated I_SOC in PAECs, and revealed I_SOC in PMVECs. Rolipram pretreatment shifted the thapsigargin-induced fluid leak site from extra-alveolar to alveolar vessels in the intact pulmonary circulation. Thus, our results indicate I_SOC provides a [Ca²⁺]_i source that is needed to disrupt the endothelial cell barrier, and demonstrate that intracellular events controlling I_SOC activation coordinate the site-specific vascular response to inflammation.

Key Words: store-operated calcium entry • thapsigargin • rolipram • permeability • phosphodiesterase

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