title: Nogo-A is a negative regulator of CNS angiogenesis.
abstract: Nogo-A is an important axonal growth inhibitor in the adult and developing CNS. In vitro, Nogo-A has been shown to inhibit migration and cell spreading of neuronal and nonneuronal cell types. Here, we studied in vivo and in vitro effects of Nogo-A on vascular endothelial cells during angiogenesis of the early postnatal brain and retina in which Nogo-A is expressed by many types of neurons. Genetic ablation or virus-mediated knock down of Nogo-A or neutralization of Nogo-A with an antibody caused a marked increase in the blood vessel density in vivo. In culture, Nogo-A inhibited spreading, migration, and sprouting of primary brain microvascular endothelial cells (MVECs) in a dose-dependent manner and induced the retraction of MVEC lamellipodia and filopodia. Mechanistically, we show that only the Nogo-A-specific Delta 20 domain exerts inhibitory effects on MVECs, but the Nogo-66 fragment, an inhibitory domain common to Nogo-A, -B, and -C, does not. Furthermore, the action of Nogo-A Delta 20 on MVECs required the intracellular activation of the Ras homolog gene family, member A (Rho-A)-associated, coiled-coil containing protein kinase (ROCK)-Myosin II pathway. The inhibitory effects of early postnatal brain membranes or cultured neurons on MVECs were relieved significantly by anti-Nogo-A antibodies. These findings identify Nogo-A as an important negative regulator of developmental angiogenesis in the CNS. They may have important implications in CNS pathologies involving angiogenesis such as stroke, brain tumors, and retinopathies.
authors.affiliation: Brain Research Institute, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wälchli
authors.forename: Vincent
authors.initials: V
authors.lastname: Pernet
authors.forename: Oliver
authors.initials: O
authors.lastname: Weinmann
authors.forename: Jau-Ye
authors.initials: JY
authors.lastname: Shiu
authors.forename: Anna
authors.initials: A
authors.lastname: Guzik-Kornacka
authors.forename: Guillaume
authors.initials: G
authors.lastname: Decrey
authors.forename: Deniz
authors.initials: D
authors.lastname: Yüksel
authors.forename: Hannah
authors.initials: H
authors.lastname: Schneider
authors.forename: Johannes
authors.initials: J
authors.lastname: Vogel
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
authors.forename: Viola
authors.initials: V
authors.lastname: Vogel
authors.forename: Karl
authors.initials: K
authors.lastname: Frei
authors.forename: Martin E
authors.initials: ME
authors.lastname: Schwab
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000166:cytology / Q000254:growth & development*; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D000070798:Nogo Proteins
chemical_list: D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603201:Rtn4 protein, mouse
keywords: developmental neuroscience; endothelial tip cells; neurovascular link