Pressure-induced upregulation of preproendothelin-1 and endothelin B receptor expression in rabbit jugular vein in situ : implications for vein graft failure?
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 micromol/L), the specific protein kinase C inhibitor, Ro 31-8220 (0.1 micromol/L), or the c-Src family-specific tyrosine kinase inhibitor, herbimycin A (0.1 micromol/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.
Lauth
M
M
Department of Cardiovascular Physiology, University of Goettingen, Goettingen, Germany.
Berger
M M
MM
Cattaruzza
M
M
Hecker
M
M
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D001483:Base Sequence; D016227:Benzoquinones; D017931:DNA Primers / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D019332:Endothelin-1 / Q000096:biosynthesis; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007601:Jugular Veins / Q000378:metabolism* / Q000637:transplantation*; D047029:Lactams, Macrocyclic; D008297:Male; D008666:Metalloendopeptidases; D011312:Pressure; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics*; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics*; D017828:Rifabutin / Q000031:analogs & derivatives; D013314:Stress, Mechanical; D015854:Up-Regulation
D016227:Benzoquinones; D017931:DNA Primers; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011498:Protein Precursors; D011809:Quinones; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D003609:Dactinomycin; D017828:Rifabutin; C020754:herbimycin; D011494:Protein Kinases; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes