Role of nitric oxide in regulating neonatal porcine pulmonary artery smooth muscle cell proliferation.

Academic Article

Abstract

  • Nitric oxide (NO), which is known to inhibit systemic vascular smooth muscle cell proliferation, is used in the management of neonatal pulmonary hypertension. Our objectives were to determine: (1) if endogenous NO production by neonatal porcine pulmonary artery smooth muscle cells (PASMCs) varied with oxygen tension in vitro, and (2) the effect of exogenous NO and inducible NO synthase (iNOS) stimulators and inhibitors on PASMC proliferation and apoptosis. PASMCs were exposed to different conditions (varying PO(2), NO donors and scavengers, iNOS stimulators and inhibitors) and proliferation, apoptosis, and cyclic guanosine 5(')-monophosphate (cGMP) assessed. PASMCs proliferated best between 5 and 10% O(2) but cGMP levels were similar at all oxygen levels. NO donors (S-nitroso-N-acetyl-penicillamine, NOC-12, NOC-18) inhibited PASMC proliferation in a dose-dependent manner with associated cGMP increases, while NO scavengers (carboxy-PTIO), iNOS stimulators (interleukin-1beta, lipopolysaccharide), and iNOS inhibitors (aminoethylisothiourea) did not affect proliferation or cGMP. No changes in apoptosis were found at the concentrations of NO donors or iNOS stimulators used. These results suggest that while exogenous NO inhibits PASMC proliferation, endogenous NO may not regulate proliferation during changes in oxygen tension or cytokine levels. Endothelial derived and inhaled NO may attenuate smooth muscle hyperplasia and vascular remodeling. Inducible NOS in porcine PASMCs appears resistant to stimulation with interleukin-1beta or lipopolysaccharide. The mechanisms underlying hypoxia-mediated changes in PASMC proliferation require investigation.
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    Keywords

  • Animals, Animals, Newborn, Apoptosis, Cell Division, Cells, Cultured, Cyclic GMP, DNA Damage, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Developmental, Immunohistochemistry, Interleukin-1, Lipopolysaccharides, Muscle, Smooth, Vascular, Nitrates, Nitric Oxide, Nitric Oxide Donors, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Nitroso Compounds, Oxygen, Penicillamine, Phosphodiesterase Inhibitors, Pulmonary Artery, Purinones, Swine
  • Digital Object Identifier (doi)

    Author List

  • Ambalavanan N; Mariani G; Bulger A; Philips III JB
  • Start Page

  • 291
  • End Page

  • 300
  • Volume

  • 76
  • Issue

  • 5