NMDA receptor crosstalk with PDGFR-β and BMPR2 is involved in smooth muscle cell proliferation in pulmonary arterial hypertension

Pulmonary Arterial Hypertension (PAH) is due to remodeling and obstruction of small pulmonary vessels, leading to right heart hypertrophy and death. Remodeling involves smooth muscle cells (SMCs) overproliferation. We have previously shown that NMDA receptor (NMDAR) is expressed by pulmonary SMCs and contributes to their proliferation in PAH. In neurons, Src has been described as a hub for signaling pathways enhancing NMDAR activity. Besides in PAH, Src is known to dysregulate vascular processes, especially vascular cell proliferation. Src has been identified as a binding partner of the C-terminus of BMPR2 (Wong, W.K. et al. AJRCMB. 2005), a protein encoded by the BMPR2 gene which is the main genetic factor of susceptibility in PAH. In addition, Src activity is enhanced by PDGFR-β signaling which is increased in PAH (Perros, F. et al. AJRCCM. 2008). We hypothesized that both BMPR2 impaired signaling and PDGFR-βoveractivation lead to increased Src activationin PAH, thus enhancing the NMDAR activity and leading to SMCs proliferation. Phosphorylation levels were assessed by western blot in explanted lungs of PAH patients and in pulmonary arterial SMCs. Interaction between different partners was studied by immunoprecipitation and immunostainings. We demonstrate that PAH patients show increased Src and NMDAR subunits (GluN2) phosphorylation. BMP2 stimulation decreases Src and GluN2B activation, whereas PDGF stimulation enhances Src, GluN2A and GluN2B phosphorylations in a time-dependent manner, possibly promoting NMDAR subunits trafficking. Thus vascular remodeling in PAH could involve BMPR2-PDGFR-β-NMDAR crosstalk through Src mobilization.