Fluid shear stress induces endothelial transforming growth factor beta-1 transcription and production. 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 TGF beta 1 via a signal transduction pathway modulated by K+ channel currents. Although TGF beta 1 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 TGF beta 1. This increase in active TGF beta 1 was associated with a sustained increase in TGF beta 1 mRNA expression within 2 h of stimulation. TGF beta 1 mRNA levels increased in direct proportion to the intensity of the shear stress within the physiologic range. The effect of shear stress on TGF beta 1 mRNA expression was regulated at the transcriptional level as defined by nuclear run-off studies and transient transfection of a TGF beta 1 promoter-reporter gene construct. Blockade of endothelial K+ channels with tetraethylammonium significantly inhibited: activation of TGF beta 1 gene transcription; increase in steady state mRNA levels; and generation of active TGF beta 1 in response to shear stress. These data suggest that endothelial K+ channels and autocrine-paracrine TGF beta 1 may be involved in the mechanotransduction mechanisms mediating flow-induced vascular remodeling.
Ohno
M
M
Division of Cardiovascular Medicine, Stanford University School of Medicine, California 94305.
Cooke
J P
JP
Dzau
V J
VJ
Gibbons
G H
GH
D000818:Animals; D001011:Aorta / Q000166:cytology; D001681:Biological Assay; D015152:Blotting, Northern; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D010812:Physical Stimulation; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012333:RNA, Messenger; D013757:Tetraethylammonium Compounds; D016212:Transforming Growth Factor beta; D019789:Tetraethylammonium