© 2000 American Heart Association, Inc.
Vascular Biology |
Pressure-Induced Upregulation of Preproendothelin-1 and Endothelin B Receptor Expression in Rabbit Jugular Vein In Situ
Implications for Vein Graft Failure?
From the Department of Cardiovascular Physiology, University of Goettingen, Goettingen, Germany.
Correspondence to Markus Hecker, PhD, Department of Cardiovascular Physiology, University of Goettingen, Humboldtallee 23, 37073 Goettingen, Germany. E-mail hecker{at}veg-physiol.med.uni-goettingen.de
Abstract—Upregulation of endothelin-1 (ET-1) synthesis in venous bypass grafts in response to arterial levels of blood pressure may play a major role in graft failure. To investigate this hypothesis, isolated segments of the rabbit jugular vein were perfused at physiological (0 to 5 mm Hg) and nonphysiological (20 mm Hg) levels of intraluminal pressure. As judged by reverse transcription–polymerase chain reaction analysis (mRNA level), neither endothelin-converting enzyme nor endothelin A receptor expression appeared to be pressure sensitive. In contrast, there was a profound and time-dependent increase in endothelial prepro-ET-1 mRNA and intravascular ET-1 abundance (by ELISA) as well as in smooth muscle endothelin B receptor mRNA and functional protein (by superfusion bioassay) on raising the perfusion pressure from 5 to 20 mm Hg, but not from 0 to 5 mm Hg, for up to 12 hours. Video microscopy analysis revealed that the segments were distended by 75% at 5 mm Hg and near maximally at 20 mm Hg compared with the resting diameter at 0 to 1 mm Hg. Treatment of the segments with actinomycin D (1 µmol/L), the specific protein kinase C inhibitor, Ro 31–8220 (0.1 µmol/L), or the c-Src family–specific tyrosine kinase inhibitor, herbimycin A (0.1 µmol/L), demonstrated that the pressure-induced expression of these gene products occurs at the level of transcription and requires activation of protein kinase C, but not c-Src. In venous bypass grafts such deformation-induced changes in gene expression may contribute not only to acute graft failure through ET-1–induced vasospasm but also to endothelin A receptor– and/or endothelin B receptor–mediated smooth muscle cell hyperplasia and graft occlusion.
Key Words: blood pressure • endothelin-1 • endothelin B receptor • gene expression • graft failure
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