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Oxygen-dependent PAF receptor binding and intracellular signaling in ovine fetal pulmonary vascular smooth muscle

Department of Pediatrics, University of California, Los Angeles, School of Medicine, Harbor-UCLA Research and Education Institute, Torrance, California

Submitted 14 September 2004 ; accepted in final form 22 December 2004

Circulating levels of platelet-activating factor (PAF) are high in the fetus, and PAF is active in maintaining high PVR in fetal hypoxia (Ibe BO, Hibler S, Raj J. J Appl Physiol 85: 1079–1085, 1998). PAF synthesis by fetal pulmonary vascular smooth muscle cells (PVSMC) is high in hypoxia, but how oxygen tension affects PAF receptor (PAF-r) binding in PVSMC is not known. We studied the effect of oxygen tension on PAF-r binding and signaling in fetal PVSMC. PAF binding was saturable. PAF-r density (B_max: fmol/10⁶ cells; means ± SE, n = 6), 25.2 ± 0.77 during hypoxia (PO₂ <40 Torr), was higher than 13.9 ± 0.44 during normoxia (PO₂ 100 Torr). K_d was twofold lower in hypoxia than normoxia. PAF-r protein expression, 35–40% greater in hypoxia, was inhibited by cycloheximide, a protein synthesis inhibitor, suggesting translational regulation. IP₃ release, an index of PAF-r-mediated cell signaling, was greater in hypoxia (EC₅₀: hypoxia, 2.94 ± 0.61; normoxia, 5.85 ± 0.51 nM). Exogenous PAF induced 50–90% greater intracellular calcium flux in cells during hypoxia, indicating hypoxia augments PAF-r-mediated cell signaling. PAF-r phosphorylation, with or without 5 nM PAF, was 40% greater in hypoxia. These data show 1) hypoxia upregulates PAF-r binding, PAF-r phosphorylation, and PAF-r-mediated intracellular signaling, evidenced by augmented IP₃ production and intracellular Ca²⁺ flux; and 2) hypoxia-induced PAF-r phosphorylation results in activation of PAF-r-mediated signal transduction. The data suggest the fetal hypoxic environment facilitates PAF-r binding and signaling, thereby promoting PAF-mediated pulmonary vasoconstriction and maintenance of high PVR in utero.

receptor phosphorylation; calcium; inositol phosphates; hypoxia; vasomotor tone; platelet-activating factor

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