Differential modulation of transendothelial electrical resistance by TRPV4 agonists is mediated by apoptosis and/or necrosis |
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Authors: | N Pairet S Mang T Kiechle N Laufhäger P Dietl DJ Lamb |
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Institution: | 1. Immunology & Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, D-88397, Biberach an der Riß, Germany;2. Institute of Immunology, Hannover Medical School, D-30625, Hannover, Germany;3. Institute of General Physiology, University of Ulm, Ulm, Germany;4. Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, D-88397, Biberach an der Riß, Germany |
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Abstract: | Transient receptor potential vanilloid 4 (TRPV4) has been implicated in many disease conditions also in the lung. Its activation leads to an increase endothelial permeability in an intracellular calcium-influx dependent manner. We investigated its function in vitro on primary human endothelial cells using two TRPV4 agonists, GSK1016790A and 4α-Phorbol 12,13-didecanoate (4α-PDD) and a selective TRPV4 blocker GSK2193874. Both TRPV4 agonists leaded to a reduction in transendothelial electrical resistance (TER) which was mediated however by differential cytotoxic effects. 4α-PDD induced apoptosis that could not be blocked by TRPV4 inhibition in HUVECs, whereas GSK1016790A selectively activated TRPV4 and reduced TER as a consequence of cellular necrosis. TRPV4 mediated cytotoxicity is poorly described and may provide significant context to the role of TRPV4 in barrier-function. |
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