title: Voltage-dependent anion channel-2 interaction with nitric oxide synthase enhances pulmonary artery endothelial cell nitric oxide production.
abstract: Increased pulmonary artery endothelial cell (PAEC) endothelium-dependent nitric oxide synthase (eNOS) activity mediates perinatal pulmonary vasodilation. Compromised eNOS activity is central to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN). Voltage-derived anion channel (VDAC)-1 was recently demonstrated to bind eNOS in the systemic circulation. We hypothesized that VDAC isoforms modulate eNOS activity in the pulmonary circulation, and that decreased VDAC expression contributes to PPHN. In PAECs derived from an ovine model of PPHN: (1) there is eNOS activity, but not expression; and (2) VDAC1 and -2 proteins are decreased. Immunocytochemistry, coimmunoprecipitation, and in situ proximity ligation assays in human PAECs (hPAECs) demonstrate binding between eNOS and both VDAC1 and -2, which increased upon stimulation with NO agonists. The ability of agonists to increase the eNOS/VDAC interaction was significantly blunted in hypertensive, compared with normotensive, ovine PAECs. Depletion of VDAC2, but not VDAC1, blocked the agonist-induced increase in eNOS activity in hPAECs. Overexpression of VDAC2 in hypertensive PAECs increased eNOS activity. Binding of VDAC2 enhances eNOS activity in the pulmonary circulation, and diminished VDAC2 constrains eNOS in PAECs derived from fetal lambs with chronic intrauterine pulmonary hypertension. We speculate that decreases in VDAC2 may contribute to the limited eNOS activity that characterizes pulmonary hypertension.
authors: Center of Excellence in Pulmonary Biology, Divisions of Pediatric Pulmonary, Asthma and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Cristina M
authors: CM
authors: Alvira
authors: Anita
authors: A
authors: Umesh
authors: Cristiana
authors: C
authors: Husted
authors: Lihua
authors: L
authors: Ying
authors: Yanli
authors: Y
authors: Hou
authors: Shu-Chen
authors: SC
authors: Lyu
authors: Jeffrey
authors: J
authors: Nowak
authors: David N
authors: DN
authors: Cornfield
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology; D015870:Gene Expression; D006632:Histamine / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010547:Persistent Fetal Circulation Syndrome / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011651:Pulmonary Artery / Q000473:pathology*; D012756:Sheep; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism; D050996:Voltage-Dependent Anion Channel 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C494762:VDAC1 protein, human; C494765:VDAC2 protein, human; D050996:Voltage-Dependent Anion Channel 2; D000001:Calcimycin; D006632:Histamine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D050995:Voltage-Dependent Anion Channel 1