Endothelial cell‐specific STIM1 deletion prevents lung vascular leak

Abstract

BackgroundThe calcium‐sensor protein, Stromal Interaction Molecule 1 (STIM1), is critical for activation of store‐operated calcium entry (SOCE) through Orai1 and TRPC channels in endothelial cells (ECs). We showed that activation of ECs by thrombin caused increased cytosolic Ca2+ ([Ca2+]i) via SOCE, but STIM1's role in mediating thrombin‐induced Ca2+ entry and its effect on endothelial permeability is unknown. In this study, we compare lung edemagenesis in normal and endothelial cell‐specific STIM1 knockout (STIM1EC−/−) mice.ResultsTo determine the in vivo functional role of STIM1 in ECs, we generated STIM1EC−/− mice by crossing STIM1fl/fl mice with Tie2 promoter‐driven‐Cre transgenic mice. STIM1EC−/− mice developed normally. In lung tissue, mRNA and protein expression of STIM1 was drastically reduced in STIM1EC−/− mice compared to STIM1fl/fl (wild type [WT]) mice. Interestingly, protein expression of Orai1 and TRPC4 was also reduced in lungs of STIM1EC−/− mice. Next, we measured PAR‐1 agonist peptide (TFLLRNPNDK‐NH2) effects on lung microvessel filtration coefficient (Kf,c), a measure of vascular permeability, in isolated lung preparations. In WT mice, PAR‐1 agonist peptide produced a 3‐ to 4‐fold increase in Kf,c over basal in 15 min. PAR‐1 effects were completely blocked in STIM1EC−/− mice.ConclusionResults suggest that STIM1 signaling in ECs regulates lung vascular leak.