Modulation by Potassium Channel Blockade

The endothelium has the capacity to modulate vascular structure in response to hemodynamic stimuli. We tested the hypothesis that exposure of the endothelium to increased laminar shear stress induces the expression of TGFp1 via a signal transduction pathway modulated by K+ channel currents. Although TGFp1 is normally secreted in a latent, inactive form, exposure of cultured endothelial cells to steady laminar shear stress (20 dynes/cm2) induced increased generation of biologically active TGFfi1. This increase in active TGFp1 was associated with a sustained increase in TGFB1 mRNA expression within 2 h of stimulation. TGFI31 mRNA levels increased in direct proportion to the intensity of the shear stress within the physiologic range. The effect of shear stress on TGFp1 mRNA expression was regulated at the transcriptional level as defined by nuclear run-off studies and transient transfection of a TGF,1 promoter-reporter gene construct. Blockade of endothelial K+ channels with tetraethylammonium significantly inhibited: activation of TGFfJ1 gene transcription; increase in steady state mRNA levels; and generation of active TGFp1 in response to shear stress. These data suggest that endothelial K+ channels and autocrine-paracrine TGF,B1 may be involved in the mechanotransduction mechanisms mediating flow-induced vascular remodeling. (J. Clin. Invest. 1995. 95:1363-1369.)