RT Journal Article
SR Electronic
T1 Role of NMDA receptors in vascular remodelling associated to pulmonary hypertension
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P314
VO 44
IS Suppl 58
A1 Sébastien J. Dumas
A1 Frédéric Perros
A1 Gilles Bru-Mercier
A1 Benoit Ranchoux
A1 Catherine Rücker-Martin
A1 Elodie Gouadon
A1 Matthieu Vocelle
A1 Peter Dorfmüller
A1 Elie Fadel
A1 Marc Humbert
A1 Sylvia Cohen-Kaminsky
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P314.abstract
AB BackgroundVascular cells express the NMDA receptor (NMDAR) but whether this glutamate receptor participates to the development of pulmonary arterial hypertension (PAH) is unknown.Aims1) Highlight components of glutamatergic communication in pulmonary vascular cells. 2) Search for deregulation of this signalling pathway in PAH. 3) Study the contribution of pulmonary arterial smooth muscle cell (PASMC) NMDAR to PH. 4) Assess the effects of an NMDAR antagonist on established PH.MethodsImmunohistochemistry and mass spectrometry imaging were used to detect components of glutamatergic communication in human lungs and vascular cells. A real-time enzymatic assay was used to detect glutamate release. PASMC proliferation was measured using BrdU incorporation. NMDAR knock out mice in PASMC were exposed to hypoxia for 3 weeks. The NMDAR antagonist MK-801 (3mg/kg/day) was administrated to monocrotaline (MCT) rats.Results1) Pulmonary vascular cells express NMDAR subunits, vesicular glutamate transporters, and release glutamate in a calcium-dependent way. 2) Remodeled arteries from iPAH patients contain higher level of glutamate compared to control arteries. Beside, Phospho896-GluN1 subunit of NMDAR, involved in its trafficking to the cell membrane, is present in vascular lesions from iPAH patients but not in controls. 3) NMDAR activation participates to PASMC proliferation induced by FBS or PDGF-BB and knocking out NMDAR in PASMC decreases PH in hypoxic mice. 4) Administration of MK-801 reverses PH in MCT rats.ConclusionGlutamatergic signaling through pulmonary vascular NMDAR occurs in PAH pathophysiology and may represent a new therapeutic target.Support: INSERM, Univ. Paris-Sud, CCML, LabEx LERMIT, FRSR.