Essential Role of a Ca 2+ -Selective, Store-Operated Current ( I SOC ) in Endothelial Cell Permeability

Abstract

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.