Deletion of transient receptor potential canonical channel 1 prevents pulmonary vascular hyper‐permeability and edema formation secondary to cAMP activation of SPHK1 (847.4)

Transient receptor potential channel (TRPC1) mediates store operated calcium (Ca 2+ ) (SOC) entry in response to endoplasmic reticulum (ER) store depletion by IP 3 , and thereby signals the loss of endothelial barrier function. We show that pulmonary endothelial cells isolated from TRPC1 null mice failed t o increase cytosolic Ca 2+ entry, endothelial gap formation and permeability in response to thrombin and thereby rendered the mice resistant to thrombin and thapsigargin‐induced lung vascular barrier dysfunction. cAMP as well as the lipid mediator sphingosine‐1‐phosphate (S1P) stabilize adherens junctions (AJs) and prevent lung vascular permeability and inflammation. Thus, we tested the hypothesis that TRPC1 deletion enhances endothelial barrier function through induction of cAMP and S1P signaling. Intriguingly, loss of TRPC1 in lung endothelial cells augmented sphingosine kinase1 (SPHK1) activity which induces the phosphorylation of sphingosine into S1P preventing AJs disruption. We show that EPAC but not PKA induced the activation of SPHK1 in human lung endothelial cells. EPAC activation enhanced endothelial barrier function in control cells but failed to strengthen barrier function in SPHK1 knockdown cells. Our results suggest that loss of TRPC1 deletion prevents increase in endothelial permeability through EPAC up regulation of SPHK1 activity. Thus, specific inhibitors design to target TRPC1 channel by increasing cAMP and S1P signaling may provide resistance to inflammatory pulmonary diseases such as acute lung injury and acute respiratory distress syndrome. Grant Funding Source : NIH