https://phaidra.vetmeduni.ac.at/o:4341 Endoplasmic Reticulum Stress Induces Vasodilation in Liver Vessels That Is Not Mediated by Unfolded Protein Response Zavadskis, Sergejs Sergejs Zavadskis Shiganyan, Anna Anna Shiganyan Müllebner, Andrea Andrea Müllebner 0009-0000-2027-1607 University of Veterinary Medicine Vienna Oesterreicher, Johannes Johannes Oesterreicher Holnthoner, Wolfgang Wolfgang Holnthoner Duvigneau, Johanna Catharina Johanna Catharina Duvigneau 0000-0002-2433-3120 University of Veterinary Medicine Vienna Kozlov, Andrey V Andrey V Kozlov MDPI journal article open access eng There is a growing body of evidence that ER stress and the unfolded protein response (UPR) play a key role in numerous diseases. Impaired liver perfusion and ER stress often accompany each other in liver diseases. However, the exact impact of ER stress and UPR on the hepatic perfusion is not fully understood. The aim of this study was to disclose the effect of ER stress and UPR on the size of liver vessels and on the levels of Ca2+ and nitric oxide (NO), critical regulators of vascular tonus. This study was carried out in precisely cut liver tissue slices. Confocal microscopy was used to create 3D images of vessels. NO levels were determined either using either laser scan microscopy (LSM) in cells or by NO-analyser in medium. Ca2+ levels were analysed by LSM. We show that tunicamycin, an inducer of ER stress, acts similarly with vasodilator acetylcholine. Both exert a similar effect on the NO and Ca2+ levels; both induce significant vasodilation. Notably, this vasodilative effect persisted despite individual inhibition of UPR pathways-ATF-6, PERK, and IRE1-despite confirming the activation of UPR. Experiments with HUVEC cells showed that elevated NO levels did not result from endothelial NO synthase (eNOS) activation. Our study suggests that tunicamycin-mediated ER stress induces liver vessel vasodilation in an NO-dependent manner, which is mediated by intracellular nitrodilator-activatable NO store (NANOS) in smooth muscle cells rather than by eNOS. Endoplasmic Reticulum Stress Unfolded Protein Response Ex-vivo Model Vascular Tonus Ca2+ NO Nitrodilators http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:4341/download 10.3390/ijms25073865 https://phaidra.vetmeduni.ac.at/o:605 application/pdf International Journal of Molecular Sciences issn:1422-0067 VoR International Journal of Molecular Sciences 25 7 4.28 MB 2024