© 2002 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Up-regulation of endothelial stretch-activated cation channels by fluid shear stress
aDepartment of Nephrology, Universitätsklinikum Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany
bDepartment of Gynecology, MC Benjamin Franklin, Freie Universität, Berlin, Germany
* Corresponding author. Tel.: +49-30-8445-2389; fax: +49-30-8445-4141 hoy{at}zedat.fu-berlin.de
Objective: Stretch-activated cation channels (SAC) have been suggested to act as endothelial mechanosensors for hemodynamic forces. Ca2+ influx through SAC could induce an intracellular Ca2+ signal stimulating Ca2+-dependent synthesis of vasodilators like NO, prostacyclin, or EDHF. In the present study we tested whether laminar shear stress (LSS) regulates SAC function. Methods: Electrophysiological properties of SAC were investigated in human umbilical vein endothelial cells (HUVEC) subjected to defined levels of LSS in a flow-cone apparatus. Results: In HUVEC, we identified a Ca2+ permeable SAC that was activated by membrane stretch. Single-channel current densities of SAC in cell-attached patches were significantly increased in HUVEC exposed to an LSS of 5 dyn/cm2 for 4 h (1.15±0.17 SAC/patch) compared to HUVEC kept in stationary culture (0.46±0.07 SAC/patch). Exposure of HUVEC to a higher LSS of 15 dyn/cm2 for 4 h induced similar up-regulation of SAC (1.27±0.21 SAC/patch). After 24 h exposure to LSS of 15 dyn/cm2, single-channel current densities of SAC remained up-regulated (1.07±0.18 SAC/patch) compared to controls. In addition, stretch-sensitivity of SAC (channel activity NPo at –30 mmHg) significantly increased after 2 h of exposure to LSS of 5 and 15 dyn/cm2 and remained up-regulated after 24 h. Inhibition of protein kinases and tyrosine kinases by H7 and genistein, respectively, prevented LSS-induced alteration of SAC function. Conclusion: Single-channel current density and mechanosensitivity of SAC in HUVEC is up-regulated by LSS. Up-regulation of SAC function leads to enhanced mechanosensitive Ca2+ influx, and represents a novel adaptive mechanism of the endothelium in the presence of altered hemodynamic forces.
KEYWORDS Endothelial function; Hemodynamics; Hypertension; Ion channels; Mechanotransduction
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