PT  - JOURNAL ARTICLE
AU  - Sébastien J. Dumas
AU  - Frédéric Perros
AU  - Gilles Bru-Mercier
AU  - Benoit Ranchoux
AU  - Catherine Rücker-Martin
AU  - Elodie Gouadon
AU  - Matthieu Vocelle
AU  - Peter Dorfmüller
AU  - Elie Fadel
AU  - Marc Humbert
AU  - Sylvia Cohen-Kaminsky
TI  - Role of NMDA receptors in vascular remodelling associated to pulmonary hypertension
DP  - 2014 Sep 01
TA  - European Respiratory Journal
PG  - P314
VI  - 44
IP  - Suppl 58
4099  - http://erj.ersjournals.com/content/44/Suppl_58/P314.short
4100  - http://erj.ersjournals.com/content/44/Suppl_58/P314.full
SO  - Eur Respir J2014 Sep 01; 44
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.