Abstract
Background
Vascular cells express the NMDA receptor (NMDAR) but whether this glutamate receptor participates to the development of pulmonary arterial hypertension (PAH) is unknown.
Aims
1) 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.
Methods
Immunohistochemistry 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.
Results
1) 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.
Conclusion
Glutamatergic 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.
- © 2014 ERS