NMDA receptor activation promotes vascular remodeling and pulmonary arterial hypertension
S. Dumas (Le Plessis Robinson,, France), G. Bru-Mercier (Le Plessis Robinson,, France), A. Courboulin (Le Plessis Robinson,, France), M. Quatredeniers (Le Plessis Robinson,, France), C. Rucker-Martin (Le Plessis Robinson,, France), F. Antigny (Le Plessis Robinson,, France), M. Nakhleh (Le Plessis Robinson,, France), B. Ranchoux (Le Plessis Robinson,, France), E. Gouadon (Le Plessis Robinson,, France), M. Vinhas (Le Plessis Robinson,, France), M. Vocelle (Le Plessis Robinson,, France), N. Raymond (Le Plessis Robinson,, France), P. Dorfmuller (Le Plessis Robinson,, France), E. Fadel (Le Plessis Robinson,, France), F. Perros (Le Plessis Robinson,, France), M. Humbert (Le Kremlin-Bicetre, France), S. Cohen-Kaminsky (Le Plessis Robinson,, France)
Source: International Congress 2018 – Pathobiology of pulmonary hypertension
Session: Pathobiology of pulmonary hypertension
Session type: Poster Discussion
Number: 3938
Disease area: Pulmonary vascular diseases
Abstract Pulmonary vascular remodeling in PAH may be driven by metabolic reprogramming of vascular cells.The NNMDA receptor (NMDAR), a major neuronal glutamate receptor, is also expressed on vascular cells but its role in PAH is unknown. Immunohistochemistry, mass spectrometry imaging and western blots were used to assess NMDAR-dependent glutamatergic communication in PAH lungs. Enzymatic assays were used to quantify glutamate release. Proliferation was measured using a BrdU assay. SMC-restricted NMDAR KO mice and NMDAR blockade in MCT rats were used to assess the role of NMDARs in vascular remodeling. We report glutamate accumulation, NMDAR upregulation and its engagement (through 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 pathways. The PDGF-BB-induced proliferation of PASMCs involved NMDAR activation -and 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. 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.
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S. Dumas (Le Plessis Robinson,, France), G. Bru-Mercier (Le Plessis Robinson,, France), A. Courboulin (Le Plessis Robinson,, France), M. Quatredeniers (Le Plessis Robinson,, France), C. Rucker-Martin (Le Plessis Robinson,, France), F. Antigny (Le Plessis Robinson,, France), M. Nakhleh (Le Plessis Robinson,, France), B. Ranchoux (Le Plessis Robinson,, France), E. Gouadon (Le Plessis Robinson,, France), M. Vinhas (Le Plessis Robinson,, France), M. Vocelle (Le Plessis Robinson,, France), N. Raymond (Le Plessis Robinson,, France), P. Dorfmuller (Le Plessis Robinson,, France), E. Fadel (Le Plessis Robinson,, France), F. Perros (Le Plessis Robinson,, France), M. Humbert (Le Kremlin-Bicetre, France), S. Cohen-Kaminsky (Le Plessis Robinson,, France). NMDA receptor activation promotes vascular remodeling and pulmonary arterial hypertension. 3938
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