Platelet‐activating factor stimulates ovine foetal pulmonary vascular smooth muscle cell proliferation: role of nuclear factor‐kappa B and cyclin‐dependent kinases

.  Objective : Platelet‐activating factor (PAF) is implicated in pathogenesis of persistent pulmonary hypertension of the neonate (PPHN); PAF is a mitogen for lung fibroblasts. PAF's role in pulmonary vascular smooth muscle cell (PVSMC) proliferation and in hypoxia‐induced pulmonary vein (PV) remodelling has not been established and mechanisms for PAF's cell‐proliferative effects are not well understood. We investigated involvement of PAF and PAF receptors in PVSMC proliferation. Materials and methods : Cells from pulmonary arteries (SMC‐PA) and veins (SMC‐PV) were serum starved for 72 h in 5% CO 2 in air (normoxia). They were cultured for 24 h more in normoxia or 2% O 2 (hypoxia) in 0.1% or 10% foetal bovine serum with 5 µCi/well of [ 3 H]‐thymidine, with and without 10 n m PAF. Nuclear factor‐kappa B (NF‐κB), CDK2 and CDK4 protein expression, and their roles in cell proliferation control were studied. Results : PAF and hypoxia increased SMC‐PA and SMC‐PV proliferation. WEB2170 inhibited PAF‐induced cell proliferation while lyso‐PAF had no effect. SMC‐PV proliferated more than SMC‐PA and PAF plus hypoxia augmented NF‐κB protein expression. NF‐κB inhibitory peptide attenuated PAF‐induced cell proliferation by 50% and PAF increased CDK2 and CDK4 protein expression. The data show that hypoxia and PAF up‐regulate PVSMC proliferation via PAF receptor‐specific pathway involving NF‐κB, CDK2 and CDK4 activations. Conclusion : They suggest that in vivo , in foetal lung low‐oxygen environment, where PAF level is high, proliferation of PVSMC will occur readily to modulate PV development and that failure of down‐regulation of PAF effects postnatally may result in PPHN.