Document Detail

Neurotrophins induce nitric oxide generation in human pulmonary artery endothelial cells.
MedLine Citation:
PMID:  21498417     Owner:  NLM     Status:  MEDLINE    
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 RESULTS: In 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(G)-nitro-L-arginine 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.
CONCLUSION: These results indicate that NTs acutely modulate pulmonary endothelial NO production and contribute to relaxation of the pulmonary vasculature.
Lucas W Meuchel; Michael A Thompson; Steven D Cassivi; Christina M Pabelick; Y S Prakash
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-04-14
Journal Detail:
Title:  Cardiovascular research     Volume:  91     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-17     Completed Date:  2011-12-30     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  668-76     Citation Subset:  IM    
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MeSH Terms
Acetylcholine / pharmacology
Brain-Derived Neurotrophic Factor / pharmacology*
Cells, Cultured
Endothelial Cells / metabolism*
Neurotrophin 3 / pharmacology*
Nitric Oxide / biosynthesis*
Nitric Oxide Synthase Type III / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Pulmonary Artery / metabolism*
RNA, Small Interfering / genetics
Receptor, Nerve Growth Factor / physiology
Receptor, trkB / physiology
Grant Support
Reg. No./Substance:
0/Brain-Derived Neurotrophic Factor; 0/Neurotrophin 3; 0/RNA, Small Interfering; 0/Receptor, Nerve Growth Factor; 31C4KY9ESH/Nitric Oxide; EC Oxide Synthase Type III; EC, trkB; EC Proteins c-akt; N9YNS0M02X/Acetylcholine

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