18 February 2018

NMDA-type glutamate receptor activation promotes vascular remodeling and pulmonary arterial hypertension

Background

Pulmonary vascular remodeling in PAH may be driven by metabolic reprogramming of vascular cells to increase glutaminolysis and glutamate production. The N-methyl-D-aspartate receptor (NMDAR), a major neuronal glutamate receptor, is also expressed on vascular cells but its role in PAH is unknown.

Methods

Immunohistochemistry, mass spectrometry imaging and western blots were used to assess the status of the NMDAR-dependent glutamatergic communication in PAH lungs. Enzymatic assays were used to detect glutamate release from vascular cells. PASMC proliferation was measured using a BrdU assay. SMC-restricted NMDAR knockout mice exposed to hypoxia for 3 weeks and blockade of NMDAR (MK-801) in MCT rats were used to emphasize the role of PASMC NMDARs in vascular remodeling. Human and animal studies were approved by ethical committees.

Results

We report glutamate accumulation, NMDAR upregulation and its engagement (reflected by increases in GluN1-subunit phosphorylation), in the pulmonary arteries of PAH patients. Kv channel inhibition and ETAR activation amplified calcium-dependent glutamate release from PASMCs, and ETAR and PDGFR activation led to NMDAR engagement, highlighting crosstalk between the glutamate-NMDAR axis and major PAH-associated pathways. The PDGF-BB-induced proliferation of PASMCs, involved NMDAR activation and phosphorylated GluN1 localization to cell-cell contacts, consistent with glutamatergic communication between proliferating PASMCs via NMDARs. Smooth-muscle NMDAR deficiency in mice attenuated the vascular remodeling triggered by chronic hypoxia. Pharmacological NMDAR blockade in MCT rats had beneficial effects on cardiac and vascular remodeling, decreasing endothelial dysfunction, cell proliferation and apoptosis resistance, while disrupting the glutamate-NMDAR pathway in pulmonary arteries.

Conclusions

These results reveal a dysregulated glutamate-NMDAR axis in the pulmonary arteries of PAH patients, and identify vascular NMDARs as targets for anti-remodeling treatments in PAH. We are setting-up first-in-class NMDAR antagonists that do not cross the blood brain barrier for better safety, with an optimized drug candidate expected by the end of 2018.

Key Contributors

Sébastien J. Dumas1,2, Gilles Bru-Mercier1,2, Audrey Courboulin1,2, Marceau Quatredeniers, 1,2, Catherine Rücker-Martin1,2, Fabrice Antigny1,2, Morad K. Nakhleh1,2, Benoit Ranchoux1,2, Elodie Gouadon1,2, Maria-Candida Vinhas1,2, Matthieu Vocelle1,2, Nicolas Raymond1,2, Peter Dorfmüller1,2, Elie Fadel1,2, Frédéric Perros1,2, Marc Humbert1,2,3, Sylvia Cohen-Kaminsky1,2 1INSERM UMR-S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, F-92350, France. 2Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, F-94270, France. 3AP-HP Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, F-94270, France.


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