title: Nogo-A regulates vascular network architecture in the postnatal brain.
abstract: Recently, we discovered a new role for the well-known axonal growth inhibitory molecule Nogo-A as a negative regulator of angiogenesis in the developing central nervous system. However, how Nogo-A affected the three-dimensional (3D) central nervous system (CNS) vascular network architecture remained unknown. Here, using vascular corrosion casting, hierarchical, synchrotron radiation μCT-based network imaging and computer-aided network analysis, we found that genetic ablation of Nogo-A significantly increased the three-dimensional vascular volume fraction in the postnatal day 10 (P10) mouse brain. More detailed analysis of the cerebral cortex revealed that this effect was mainly due to an increased number of capillaries and capillary branchpoints. Interestingly, other vascular parameters such as vessel diameter, -length, -tortuosity, and -volume were comparable between both genotypes for non-capillary vessels and capillaries. Taken together, our three-dimensional data showing more vessel segments and branchpoints at unchanged vessel morphology suggest that stimulated angiogenesis upon Nogo-A gene deletion results in the insertion of complete capillary micro-networks and not just single vessels into existing vascular networks. These findings significantly enhance our understanding of how angiogenesis, vascular remodeling, and three-dimensional vessel network architecture are regulated during central nervous system development. Nogo-A may therefore be a potential novel target for angiogenesis-dependent central nervous system pathologies such as brain tumors or stroke.
authors.affiliation: 1 Group of CNS Angiogenesis and Neurovascular Link, and Physician-Scientist Program, Institute for Regenerative Medicine, Neuroscience Center Zurich, and Division of Neurosurgery, University and University Hospital Zurich, Switzerland, and Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.|2 Division of Neurosurgery and Laboratory of Molecular Neuro-Oncology, University Hospital Zurich, Zurich, Switzerland.|3 Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wälchli
authors.affiliation: 4 Institute of Molecular Life Sciences, University of Zürich, Zurich, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ulmann-Schuler
authors.affiliation: 5 G.tec Medical Engineering GmbH, Guger Technologies OG, Graz, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hintermüller
authors.affiliation: 3 Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Meyer
authors.affiliation: 6 Swiss Light Source, Paul Scherrer Institute, Villigen, Switzerland.|7 Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Stampanoni
authors.affiliation: 8 Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Leuven, Belgium.|9 Department of Oncology, Laboratory of Angiogenesis and Neurovascular Link, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: 10 Institute for Regenerative Medicine and Clinic for Cardiovascular Surgery, University Hospital Zurich.|11 Wyss Translational Center Zurich, University of Zurich and Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
authors.forename: Maximilian Y
authors.initials: MY
authors.lastname: Emmert
authors.affiliation: 2 Division of Neurosurgery and Laboratory of Molecular Neuro-Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bozinov
authors.affiliation: 2 Division of Neurosurgery and Laboratory of Molecular Neuro-Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Regli
authors.affiliation: 3 Brain Research Institute, University of Zurich and Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Schwab
authors.affiliation: 12 Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Vogel
authors.affiliation: 10 Institute for Regenerative Medicine and Clinic for Cardiovascular Surgery, University Hospital Zurich.|11 Wyss Translational Center Zurich, University of Zurich and Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Hoerstrup
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000098:blood supply / Q000254:growth & development*; D002540:Cerebral Cortex / Q000098:blood supply; D017353:Gene Deletion; D021621:Imaging, Three-Dimensional / Q000379:methods; D051379:Mice; D018919:Neovascularization, Physiologic; D000070798:Nogo Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D000070798:Nogo Proteins
keywords: Nogo-A; capillary micro-networks; central nervous system angiogenesis; neurovascular link; three-dimensional central nervous system vascular network architecture