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• W2014591299 abstract "Hypoxia-induced neonatal persistent pulmonary hypertension (PPHN) is characterized by sustained vasospasm and increased thromboxane (TxA 2 )-to-prostacyclin ratio. We previously demonstrated that moderate hypoxia induces myocyte TxA 2 hypersensitivity. Here, we examined TxA 2 prostanoid receptor (TP-R) localization and kinetics following hypoxia to determine the mechanism of hypoxia-induced TxA 2 hypersensitivity. Primary cultured neonatal pulmonary artery myocytes were exposed to 10% O 2 (hypoxic myocytes; HM) or 21% O 2 (normoxic myocytes; NM) for 3 days. PPHN was induced in neonatal piglets by in vivo exposure to 10% Fi O 2 for 3 days. TP-R was studied in whole lung sections from pigs with hypoxic PPHN- and age-matched controls; intracellular localization was studied by immunocytochemistry. TP-R affinity was studied in cultured myocytes by saturation binding kinetics using 3 H-SQ-29548 and competitive binding kinetics by coincubation with U-46619. Phosphorylation and coupling were examined in immunoprecipitated TP-R. We report distal propagation of TP-R expression in PPHN, extending to pulmonary arteries <50 μm. In HM, intracellular TP-R moves towards the perinuclear region, mirroring a change in endoplasmic reticulum (ER) morphology. TP-R kinetics also alter in HM membranes, with decreased K d and B max (maximal binding sites). Additionally, in hypoxia, 3 H-SQ-29548 is displaced at lower concentration of U-46619 than in normoxia, suggesting increased agonist affinity. Phosphorylation of serine residues on HM TP-R was significantly decreased compared with NM; this difference correlated with increased Gα q coupling in hypoxia and was ablated by incubation with PKA. We conclude that the TP-R is normally desensitized in the neonatal pulmonary circuit by PKA-mediated regulatory phosphorylation, decreasing ligand affinity and coupling to Gα q ; this protection is lost following hypoxic exposure. Also, the appearance of TP-R in resistance arteries after development of hypoxic PPHN may contribute to increased pulmonary arterial pressure." @default.
• W2014591299 created "2016-06-24" @default.
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• W2014591299 date "2007-03-01" @default.
• W2014591299 modified "2023-10-15" @default.
• W2014591299 title "Thromboxane hypersensitivity in hypoxic pulmonary artery myocytes: altered TP receptor localization and kinetics" @default.
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• W2014591299 doi "https://doi.org/10.1152/ajplung.00229.2006" @default.
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