Neurotrophins induce nitric oxide generation in human pulmonary artery endothelial cells

Lucas W. Meuchel, Michael A. Thompson, Steven D. Cassivi, Christina M. Pabelick, Y. S. Prakash

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Aims Members of the growth factor family of neurotrophins [NTs; e.g. brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3)] and their high-affinity receptors (tropomyosin-related kinase; Trk) and low-affinity receptors p75 neurotrophin receptor (p75NTR) have been localized to pulmonary artery (PA) in humans. However, their role is unclear. Based on previous findings of NTs and their receptors within the pulmonary endothelium, we tested the hypothesis that NTs induce nitric oxide (NO) production in pulmonary endothelial cells (ECs), thus contributing to vasodilation. Methods and resultsIn human pulmonary artery ECs loaded with the NO-sensitive fluorescent dye diaminofluorescein-2, both BDNF and NT3 (100 pM, 1 nM, and 10 nM) acutely (<10 min) and substantially increased fluorescence levels in a concentration-dependent fashion (to levels comparable to that induced by 1 μM acetylcholine). NT-induced elevation of NO levels was blunted by the tyrosine kinase inhibitor K252a, the nitric oxide synthase (NOS) inhibitor N GnitroLarginine methyl ester, the Ca 2 chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, and the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. Suppression of TrkB or TrkC expression via siRNA as well as functional blockade of p75NTR prevented NT-induced NO elevation. Both BDNF and NT3 increased phosphorylation of Akt and endothelial NO synthase (eNOS). In endothelium-intact porcine PA rings, NTs increased cGMP and induced vasodilation in pre-contracted arteries. ConclusionThese results indicate that NTs acutely modulate pulmonary endothelial NO production and contribute to relaxation of the pulmonary vasculature.

Original languageEnglish (US)
Pages (from-to)668-676
Number of pages9
JournalCardiovascular research
Volume91
Issue number4
DOIs
StatePublished - Sep 1 2011

Keywords

  • Brain-derived neurotrophic factor
  • Lung
  • Neurotrophin-3
  • Tropomyosin-related kinase
  • p75NTR

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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