Abstract
Ultrasound targeted microbubble cavitation (UTMC) enhances drug-delivery across the endothelial barrier, but the underlying molecular mechanisms require further investigation. Here we explore the role of mechanosensitive piezo1 channels in regulating UTMC-induced hyperpermeability. Human coronary artery endothelial cells on transwells showed that UTMC (1 MHz, 250 kPa, 10 cycles, 10 ms interval for 10 s) caused hyperpermeability, demonstrated by reduced transendothelial electrical resistance (TEER) (1.7-fold, p < 0.05) and increased dextran flux across the monolayer (twofold, p < 0.01 for 70 kDa dextran, 1.6-fold, p < 0.05 for 10 kDa dextran). UTMC enhanced the paracellular permeability as shown by transient increase in inter-endothelial gaps. Inhibition of Ca2+ influx using mechanosensitive channel inhibitor GsMTx4, or piezo1 siRNA abrogated UTMC-induced hyperpermeability. Reduction in Ca2+ influx diminished inter-endothelialgaps and stress-fiber formation, suggesting Ca2+ influx is required, at least in part, for UTMC-induced hyperpermeability. UTMC increased nitric oxide (NO) production and inhibition of endothelial NO synthase with L-NAME abrogated UTMC-induced hyperpermeability, indicating a role for NO. Immunostaining showed that UTMC caused reorganization of adherens-junction protein VE-cadherin from a linear to interrupted pattern, which is known to be associated with hyperpermeability. Further elucidation of these pathways will aid in clinical translation and optimization of UTMC for delivery of cell-impermeant drugs.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.