Essential role of a Ca2+-selective, store-operated current (ISOC) in endothelial cell permeability -: Determinants of the vascular leak site

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.