Fluid Shear Stress Induces Endothelial Transforming Growth Factor Beta-1 Transcription and Production: Modulation by Potassium Channel Blockade

Abstract

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 TGFβ1 via a signal transduction pathway modulated by K+ channel currents. Although TGFβ1 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 TGFβ1. This increase in active TGFβ1 was associated with a sustained increase in TGFβ1 mRNA expression within 2 h of stimulation. TGFβ1 mRNA levels increased in direct proportion to the intensity of the shear stress within the physiologic range. The effect of shear stress on TGFβ1 mRNA expression was regulated at the transcriptional level as defined by nuclear run-off studies and transient transfection of a TGFβ1 promoter-reporter gene construct. Blockade of endothelial K+ channels with tetraethylammonium significantly inhibited: activation of TGFβ1 gene transcription; increase in steady state mRNA levels; and generation of active TGFβ1 in response to shear stress. These data suggest that endothelial K+ channels and autocrine-paracrine TGFβ1 may be involved in the mechanotransduction mechanisms mediating flow-induced vascular remodeling.