Role of platelet-activating factor in pulmonary vascular remodeling associated with chronic high altitude hypoxia in ovine fetal lambs.
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 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 3,801 m (12,470 ft) altitude from approximately 35 to 145 days 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) were 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 blot analysis on lung tissue SMC-PA demonstrated greater PAF-R expression in HAH lambs. PAF-R binding (femtomoles per 10(6) 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 with controls SMC-PA of HAH lambs demonstrated 139% and 40% greater proliferation in 10% FBS alone and with 10 nM 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.
Bixby
Christine E
CE
Division of Neonatology, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Ibe
Basil O
BO
Abdallah
May F
MF
Zhou
Weilin
W
Hislop
Alison A
AA
Longo
Lawrence D
LD
Raj
J Usha
JU
D000532:Altitude Sickness / Q000503:physiopathology*; D000818:Animals; D001724:Birth Weight / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D010972:Platelet Activating Factor / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011247:Pregnancy; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D034561:Sheep, Domestic
D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor