Induction of endoplasmic reticulum stress impairs insulin-stimulated vasomotor relaxation in rat aortic rings: Role of endothelin-1

Sustained endoplasmic reticulum (er) stress and thus activation of the unfolded protein response is now thought to be the foundation of various chronic disorders including whole-body insulin resistance and cardiovascular disease. the purpose of the present study was to test the hypothesis that er stress impairs insulin-stimulated vasomotor reactivity. we report that experimental induction of er stress in isolated aortic rings with tunicamycin (20 μg/ml),a well-established inducer of er stress,resulted in insulin-stimulated vascular contraction (-78±21% at 1000 μiu/ml; -100±27% at 10,000 μiu/ml; all p<0.05) rather than relaxation (+23±7% at 1000 μiu/ml; +43±8% at 10,000 μiu/ml; all p<0.05). importantly,we found that insulin-stimulated vascular contraction as a result of er stress was largely eliminated in the presence of tezosentan (3 μm),a nonselective endothelin-1 (et-1) receptor blocker (+1±14% at 1000 μiu/ml; +8±17% at 10,000 μiu/ml). similarly,inhibition of et-1 receptors fully restored the impairment of acetylcholine-mediated relaxation induced by er stress (maximal relaxation: control = 94±2%,tunicamycin = 76±5%,tunicamycin + tezosentan = 90±3). furthermore,we demonstrate that er stress caused a ~20-fold greater release of et-1 from aortic endothelial cells under basal conditions as well as a ~15-fold increase under insulin-stimulated conditions (p<0.05). this er stress-mediated up-regulation in et-1 release from endothelial cells was accompanied by a ~3-fold increase in phosphorylation of p44/22 mapk (p<0.05),a known pathway by which insulin signaling activates et-1. together,these findings support the hypothesis that vascular er stress-mediated activation of et-1 may be an underlying cause of impaired vasomotor responsiveness to insulin and endothelial dysfunction.