Pressure-induced upregulation of preproendothelin-l and endothelin B receptor expression in rabbit jugular vein in situ - Implications for vein graftfailure?

Upregulation of endothelin-1 (ET-1) synthesis in venous bypass grafts in re sponse to arterial levels of blood pressure may play a major role in graft failure. To investigate this hypothesis, isolated segments of the rabbit ju gular vein were perfused at physiological (0 to 5 mm Hg) and nonphysiologic al (20 mm Hg) levels of intraluminal pressure. As judged by reverse transcr iption-polymerase chain reaction analysis (mRNA level), neither endothelin- converting enzyme nor endothelin A receptor expression appeared to be press ure sensitive. In contrast, there was a profound and time-dependent increas e in endothelial prepro-ET-1 mRNA and intravascular ET-1 abundance (by ELIS A) as well as in smooth muscle endothelin B receptor mRNA and functional pr otein (by superfusion bioassay) on raising the perfusion pressure from 5 to 20 mm HE, 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 ne ar maximally at 20 mm Hg compared with the resting diameter at 0 to 1 mm Hg . Treatment of the segments with actinomycin D (1 mu mol/L), the specific p rotein kinase C inhibitor, Ro 31-8220 (0.1 mu mol/L), or the c-Src family-s pecific tyrosine kinase inhibitor, herbimycin A (0.1 mu mol/L), demonstrate d that the pressure-induced expression of these gene products occurs at the level of transcription and requires activation of protein kinase C, but no t c-Src. In venous bypass grafts such deformation-induced changes in gene e xpression may contribute not only to acute graft failure through ET-1-induc ed vasospasm but also to endothelin A receptor- and/or endothelin B recepto r-mediated smooth muscle cell hyperplasia and graft occlusion.