Abstract
Neurofibromin 2 (NF2), a potent tumor suppressor, is reported to inhibit proliferation in several cell types. The role of NF2 in neointima hyperplasia after vascular injury is unknown. We explored the role of NF2 in proliferation, migration of vascular smooth muscle cell (VSMC) and neointima hyperplasia after vascular injury. NF2 phosphorylation was elevated in VSMC subjected to platelet-derived growth factor (PDGF)-BB and in artery subjected to vascular injury. Mice deficient for Nf2 in VSMC showed enhanced neointima hyperplasia after injury, increased proliferation and migration of VSMC after PDGF-BB treatment. Mechanistically, we observed increased nuclear p-NF2, declined p-Yes-Associated Protein (YAP), nuclear translocation of YAP after PDGF-BB treatment or injury. NF2 knockdown or YAP overexpression showed similar phenotype in VSMC proliferation, migration and neointima hyperplasia. YAP inhibition abolished the above effects mediated by NF2 knockdown. Finally, NF2 knockdown further promoted YAP-TEA Domain Transcription Factor 1 (TEAD1) interaction after PDGF-BB treatment. Inhibition of TEAD1 blocked PDGF-BB-induced VSMC proliferation and migration, which were not reversed by either NF2 knockdown or YAP overexpression. In conclusion, NF2 knockdown promotes VSMC proliferation, migration and neointima hyperplasia after vascular injury via inducing YAP-TEAD1 interaction.