Objective: Stretch-activated cation channels (SAC) have been suggested to act as endothelial mechanosensors for hemodynamic forces. 21 21 21 Ca influx through SAC could induce an intracellular Ca signal stimulating Ca -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)

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... ed to defined levels 21 of LSS in a flow-cone apparatus. Results: In HUVEC, we identified a Ca permeable SAC that was activated by membrane stretch. 2 Single-channel current densities of SAC in cell-attached patches were significantly increased in HUVEC exposed to an LSS of 5 dyn / cm for 4 h (1.1560.17 SAC / patch) compared to HUVEC kept in stationary culture (0.4660.07 SAC / patch). Exposure of HUVEC to a 2 higher LSS of 15 dyn / cm for 4 h induced similar up-regulation of SAC (1.2760.21 SAC / patch). After 24 h exposure to LSS of 15 2 dyn / cm , single-channel current densities of SAC remained up-regulated (1.0760.18 SAC / patch) compared to controls. In addition, 2 stretch-sensitivity of SAC (channel activity NP at 230 mmHg) significantly increased after 2 h of exposure to LSS of 5 and 15 dyn / cm o 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 21 up-regulated by LSS. Up-regulation of SAC function leads to enhanced mechanosensitive Ca influx, and represents a novel adaptive mechanism of the endothelium in the presence of altered hemodynamic forces. This article is referred to in the Editorial by K. release of nitric oxide [3, 4] , increased expression of endothelial nitric oxide synthase (NOSIII) [5, 6] , and Groschner ( pages 9 -11) in this issue. rearrangement of the actin cytoskeleton [7] within hours. In the very early cellular responses of mechanotransduci 21 the release of Ca from internal stores [9, 12, 14] and the