Regulation of the endothelin system by shear stress in human endothelial cells

1In this study, the effect of shear stress on the expression of genes of the human endothelin‐1 system was examined. Primary cultures of human umbilical vein endothelial cells (HUVEC) were exposed to laminar shear stress of 1, 15 or 30 dyn cm−2(i.e. 0.1, 1.5 or 3 N m−2) (venous and two different arterial levels of shear stress) in a cone‐and‐plate viscometer.2Laminar shear stress transiently upregulates preproendothelin‐1 (ppET‐1) mRNA, reaching its maximum after 30 min (approx 1.7‐fold increase). In contrast, long‐term application of shear stress (24 h) causes downregulation of ppET‐1 mRNA in a dose‐dependent manner.3Arterial levels of shear stress result in downregulation of endothelin‐converting enzyme‐1 isoform ECE‐1a (predominating in HUVEC) to 36.2 ± 8.5%, and isoform ECE‐1b mRNA to 72.3 ± 1.9% of static control level.4The endothelin‐1 (ET‐1) release is downregulated by laminar shear stress in a dose‐dependent manner.5This downregulation of ppET‐1 mRNA and ET‐1 release is not affected by inhibition of protein kinase C (PKC), or tyrosine kinase. Inhibition of endothelial NO synthase (L‐NAME, 500 μm) prevents downregulation of ppET‐1 mRNA by shear stress.6In contrast, increasing degrees of long‐term shear stress upregulate endothelin receptor type B (ETB) mRNA by a NO‐ and PKC‐, but not tyrosine kinase‐dependent mechanism.7In conclusion, our data suggest the downregulation of human endothelin synthesis, and an upregulation of the ETBreceptor by long‐term arterial laminar shear stress. These effects might contribute to the vasoprotective and anti‐arteriosclerotic potential of arterial laminar shear stress.