biostudies-literatureDaneva ZAmerican Heart AssociationHHS | NIH | National Heart, Lung, and Blood Institutee2023130118https://www.ebi.ac.uk/biostudies/studies/S-EPMC8092599biostudies-literatureUnknown118(17)Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolinProceedings of the National Academy of Sciences of the United States of AmericaCaveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension.PMC809259920PRE35210176HL130261HL142808HL113178HL147555HL146914Marziano CIsakson BEBaker TMSonkusare SKOttolini MMihalek ADTa HQMinshall RDKuppusamy MReagan CELaubach VEKasetti RBShen YZode GSGoncharova EADaneva ZChen YLZhang AfalseCaveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension.Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin2021-01-01T00:00:00Z2021 Apr2025-04-26T23:41:37.628Z2025-04-06T17:39:20.289ZS-EPMC80925993387961610.1073/pnas.2023130118