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.
Wu
Songwei
S
Center for Lung Biology, The University of South Alabama College of Medicine, Mobile, Ala 36688, USA.
Cioffi
Eugene A
EA
Alvarez
Diego
D
Sayner
Sarah L
SL
Chen
Hairu
H
Cioffi
Donna L
DL
King
Judy
J
Creighton
Judy R
JR
Townsley
Mary
M
Goodman
Steven R
SR
Stevens
Troy
T
D000262:Adenylyl Cyclases / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology*; D002199:Capillary Permeability; D000242:Cyclic AMP / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D007473:Ion Channels / Q000502:physiology; D007811:Lanthanum / Q000494:pharmacology; D008958:Models, Molecular; D051381:Rats; D020889:Rolipram / Q000494:pharmacology; D050052:TRPC Cation Channels; D019284:Thapsigargin / Q000494:pharmacology
D015220:Calcium Channels; D007473:Ion Channels; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; D019284:Thapsigargin; D007811:Lanthanum; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D020889:Rolipram; D002118:Calcium