Proprotein convertase furin enhances survival and migration of vascular smooth muscle cells via processing of pro-nerve growth factor

Maturation of nerve growth factor (NGF) in neuronal cells requires endoproteolytic processing of the precursor protein proNGF to beta-NGF by the proprotein convertase furin. Pro- and beta-NGF elicit opposite biological functions by differential neurotrophin-receptor binding, leading to apoptosis via sortilin or survival via neurotrophic tyrosine kinase receptor type-1 (TrkA), respectively. The present study was done to investigate the impact of furin-dependent proNGF processing on vascular smooth muscle cell (VSMC) function. We found that beta-NGF mRNA and protein expression was upregulated in platelet-derived growth factor-BB/transforming growth factor-beta 1-stimulated, proliferating rat aortic VSMCs. Although beta-NGF itself did not affect VSMC proliferation, it promoted VSMC motility in an autocrine fashion via TrkA/Akt-dependent integrin inside-out signalling. The beta-NGF-induced migration of VSMCs required proNGF processing by furin, which was co-regulated with NGF. Furin-inhibition increased proNGF and reduced beta-NGF secretion, leading to apoptosis rather than migration. In line with our in vitro demonstration, we found co- and upregulation of NGF, its convertase furin and its high-affinity receptor TrkA in the neointima of balloon-injured rodent arteries. These results indicate that furin determines the balance between proNGF and beta-NGF in proliferating VSMCs, thus impacting on VSMC survival and migration and is also important in neointima formation.