LSC Abstract – Glutamatergic signaling through pulmonary vascular NMDA receptors in pulmonary hypertension

Background: The NMDA receptor (NMDAR), a glutamate receptor, is a crucial component of neuronal synapses, but it is also described in vascular cells where its role remains elusive. Aims: 1) Highlight components of glutamatergic communication in pulmonary vascular cells. 2) Search for dysegulation of this pathway in pulmonary arterial hypertension (PAH). 3) Study the contribution of pulmonary arterial smooth muscle cell (PASMC) NMDAR to PH. 4) Assess the effects of the NMDAR antagonist MK-801 on established PH. Methods: Immunohistochemistry and mass spectrometry imaging were used to detect components of glutamatergic communication in human lungs and vascular cells. Enzymatic assays were used to detect glutamate release from vascular cells. PASMC proliferation was measured using BrdU incorporation. NMDAR knock out mice in PASMC were exposed to hypoxia for 3 weeks. MK-801 (3mg/kg/d) 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) Endothelin-1 triggers glutamate release from PASMC and NMDAR activation participates to PASMC proliferation. 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.