title: Proprotein convertase furin enhances survival and migration of vascular smooth muscle cells via processing of pro-nerve growth factor.
abstract: Maturation of nerve growth factor (NGF) in neuronal cells requires endoproteolytic processing of the precursor protein proNGF to β-NGF by the proprotein convertase furin. Pro- and β-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 β-NGF mRNA and protein expression was upregulated in platelet-derived growth factor-BB/transforming growth factor-β1-stimulated, proliferating rat aortic VSMCs. Although β-NGF itself did not affect VSMC proliferation, it promoted VSMC motility in an autocrine fashion via TrkA/Akt-dependent integrin inside-out signalling. The β-NGF-induced migration of VSMCs required proNGF processing by furin, which was co-regulated with NGF. Furin-inhibition increased proNGF and reduced β-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 β-NGF in proliferating VSMCs, thus impacting on VSMC survival and migration and is also important in neointima formation.
authors.affiliation: Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Urban
authors.forename: Janina
authors.initials: J
authors.lastname: Lorenz
authors.forename: Heike
authors.initials: H
authors.lastname: Meyborg
authors.forename: Sanchita
authors.initials: S
authors.lastname: Ghosh
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.forename: Jan
authors.initials: J
authors.lastname: Kaufmann
authors.forename: Eckart
authors.initials: E
authors.lastname: Fleck
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
authors.forename: Philipp
authors.initials: P
authors.lastname: Stawowy
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D045683:Furin / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020932:Nerve Growth Factor; D045683:Furin; D053148:Caspase 3; D053179:Caspase 7