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1 Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States
2 Division of Neonatology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, California, United States
3 Vascular Biology and Pharmacology, Institute of Child Health, London, United Kingdom
4 Department of Physiology & OB/GYN, Loma Linda University School of Medicine, Loma Linda, California, United States
5 Department of Pediatrics, Geffen School of Medicine at UCLA, Torrance, California, United States
* To whom correspondence should be addressed. E-mail: ibe{at}labiomed.org.
Platelet activating factor (PAF) is implicated in pathogenesis of chronic hypoxia-induced pulmonary hypertension in some animal models and in neonates. Effects of chronic hypoxia on PAF-PAF receptor (PAF-R) system in fetal pulmonary vasculature are unknown. We investigated the effect of chronic high altitude hypoxia (HAH) in fetal lambs (pregnant ewes were kept at 3,801m (12,470 ft) altitude from ~35d to 145d gestation), on PAF-R-mediated effects in the pulmonary vasculature. Age-matched controls were kept at sea level. Intrapulmonary arteries were isolated and smooth muscle cells (SMC-PA) cultured from HAH and control fetuses. To determine presence of pulmonary vascular remodeling, lung tissue sections were subjected to morphometric analysis. Percentage medial wall thickness was significantly increased (p<0.05) in arteries at all levels in the HAH lambs. PAF-R protein expression studied by immunocytochemistry and Western analysis on lung tissue SMC-PA demonstrated greater PAF-R expression in HAH lambs. PAF-R binding (fmol/106 cells) in HAH SMC-PA was 90.3±4.08 and 66% greater than 54.3±4.9 in control SMC-PA. Pulmonary arteries from HAH fetuses synthesized >3-fold PAF than vessels from controls Compared to controls, SMC-PA of HAH lambs demonstrated 139% and 40% greater proliferation in 10% FBS alone and with 10nM PAF, respectively. Our data demonstrate that exposure of ovine fetuses to HAH will result in significant upregulation of PAF synthesis, PAF-R expression and PAF-R-mediated effects in pulmonary arteries. These findings suggest that increased PAF-R protein expression and increased PAF binding contribute to pulmonary vascular remodeling in these animals and may predispose them to persistent pulmonary hypertension after birth.
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