Abstract
Activation of store-operated Ca2+ channels disrupts endothelial cell (EC) junctions in lung extra-alveolar vessels, while the channel responsible for Ca2+ entry-dependent injury in septal capillaries is unknown. Since 14,15-epoxyeicosatrienoic acid (14,15-EET) causes EC injury in rat lung septal capillaries and EETs activate Ca2+ entry via the vanilloid transient receptor potential channel TRPV4 in aortic EC, we tested whether activation of TRPV4 increases septal EC permeability. Lungs from anesthetized wild type mice (TRPV4+/+) and null littermates (TRPV4−/−) (22.2±0.9 g, mean±SE) were perfused at 0.055±0.002 mL/min/g body wt with 4% albumin/physiologic buffer (37 °C). EC permeability was measured via the filtration coefficient (Kf) at baseline and 45 min after treatment with 4α-phorbol-12,13-didecanoate (4αPDD, 10 μM) to activate TRPV4, thapsigargin (TG, 150 nM) to activate store-operated Ca2+ channels, or vehicle (DMSO, 50 μL). TG increased permeability by 2.8- and 3.2-fold in wild type and null groups, respectively (*p<0.05, paired t-test). In contrast, 4αPDD increased permeability by 2.9-fold in lungs from TRPV4+/+ mice, but had no impact in TRPV4−/− mice. Transmissionelectron microscopy revealed that 4αPDD resulted in blebbing of septal EC in wild type mice while extra-alveolar vessel EC junctions were intact, a pattern similar to that with 14,15-EET in rat lung. We conclude that TRPV4 constitutes a novel Ca2+ entry pathway involved in regulation of lung EC permeability in septal capillaries. Supported by HL081851 and SE AHA 0315049B.
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