Essential role of a Ca2+-selective, store-operated current (ISOC) in endothelial cell permeability: determinants of the vascular leak site. Circ Res 96

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, ISOC. Pretreatment with the type 4 phosphodiesterase inhibitor, rolipram, abolished thapsigargin-activated ISOC in PAECs, and revealed ISOC 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 ISOC provides a [Ca2]i source that is needed to disrupt the endothelial cell barrier, and demonstrate that intracellular events controlling ISOC activation coordinate the site-specific vascular response to inflammation. (Circ Res. 2005;96:856-863.) Key Words: store-operated calcium entry thapsigargin rolipram permeability phosphodiesterase Endothelium is remarkably diverse, with significant struc-tural and functional heterogeneity apparent between organs, along vascular segments, and indeed, within imme-diately adjacent cells. Relatively little is known about ho