Abstract 553: The Matricellular Protein Ccn1 is a Key Mediator of Smooth Muscle Cell Migration and Neointimal Formation

Platelet-derived growth factor (PDGF), a potent chemoattractant, induces smooth muscle cell (SMC) migration via the MAPK and PI3K/Akt pathways. However, the downstream mediators are still elusive. In particular, the role of extracellular mediators is largely unknown. In this study, we identified the matricellular protein CCN1, which is de novo synthesized in response to PDGF stimulation, as the key downstream mediator of the ERK and JNK pathways, independent of the p38 MAPK and AKT pathways, and, thereby, it mediates PDGF-induced SMC migration. Our results revealed that, when CCN1 was newly synthesized by PDGF, it was promptly translocated to the extracellular matrix and physically interacted with the plasma membrane integrins α6β1 and αvβ3. We further demonstrate that CCN1 and integrins are integral components of the PDGF signaling pathway via an “outside-in” signaling route to activate intracellular focal adhesion kinase (FAK), leading to SMC migration. Therefore, our study provides new evidence that the PDGF-induced endogenous extracellular matrix component CCN1 is a key mediator in modulating SMC migration by connecting intracellular PDGF-ERK and JNK signals with integrin/FAK signaling. Therefore, extracellular CCN1 convergence with growth factor signaling and integrin/FAK signaling is a new concept of growth factor-induced cell migration. We further identified that CCN1 is a key mediator of lysophosphatidic acid (LPA)-mediated SMC migration. Our recent data reveal that CCN1 mediates LPA-induced neointimal formation. The discovered novel signaling pathway may represent an important therapeutic target in growth factor/lipid-mediated cell migration related vascular diseases.