Functional interaction between PDGF and GluN2B-containing NMDA receptors in smooth muscle cell proliferation and migration in pulmonary arterial hypertension.

In this study, we explored the complex interactions between platelet-derived growth factor (PDGF) and N-methyl D-aspartate receptor (NMDAR), and their effect on the excessive proliferation and migration of smooth muscle cells leading to obstructed arteries in Pulmonary Arterial Hypertension (PAH). We report lower expression of GluN2B, a subunit composing NMDARs expected to affect cell survival/proliferation of pulmonary artery smooth muscle cells (PASMCs), in PAH patients' lungs. PASMCs exposure to PDGF-BB, stimulated immediate increased levels of phosphorylated Src family kinases (SFKs) together with increased phosphorylated GluN2B (its active form) and cell surface relocalization, suggesting a cross-talk between PDGFR-recruited SFKs and NMDAR. Selective inhibition of PDGFR-β or SFKs, with Imatinib or A-419259 respectively on one hand, or with specific siRNAs on the other hand, aborted PDGF-induced phosphorylation of GluN2B, thus validating the pathway. Selective inhibition of GluN2B using Rö25-6981 as well as silencing with specific siRNA, in the presence of PDGF-BB, significantly increased both migration and proliferation of PASMCs, thus strengthen the functional importance of the pathway. Together, these results indicate that GluN2B-type NMDARs activation may confer to PASMCs anti-proliferative and anti-migratory properties. The decreased levels of GluN2B observed in PAH pulmonary arteries could mediate the excessive proliferation of PASMCs, thus contributing to medial hyperplasia and PAH development.