title: Blood flow controls bone vascular function and osteogenesis.
abstract: While blood vessels play important roles in bone homeostasis and repair, fundamental aspects of vascular function in the skeletal system remain poorly understood. Here we show that the long bone vasculature generates a peculiar flow pattern, which is important for proper angiogenesis. Intravital imaging reveals that vessel growth in murine long bone involves the extension and anastomotic fusion of endothelial buds. Impaired blood flow leads to defective angiogenesis and osteogenesis, and downregulation of Notch signalling in endothelial cells. In aged mice, skeletal blood flow and endothelial Notch activity are also reduced leading to decreased angiogenesis and osteogenesis, which is reverted by genetic reactivation of Notch. Blood flow and angiogenesis in aged mice are also enhanced on administration of bisphosphonate, a class of drugs frequently used for the treatment of osteoporosis. We propose that blood flow and endothelial Notch signalling are key factors controlling ageing processes in the skeletal system.
authors.affiliation: Faculty of Medicine, Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine and University of Münster, D-48149 Münster, Germany.|Research group Integrative Skeletal Physiology, Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Saravana K
authors.initials: SK
authors.lastname: Ramasamy
authors.affiliation: Faculty of Medicine, Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine and University of Münster, D-48149 Münster, Germany.|Research group Tissue and Tumor Microenvironments, Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7LY, UK.
authors.forename: Anjali P
authors.initials: AP
authors.lastname: Kusumbe
authors.affiliation: Faculty of Medicine, Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine and University of Münster, D-48149 Münster, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Schiller
authors.affiliation: Electron Microscopy Unit, Max-Planck-Institute for Molecular Biomedicine, D-48149 Münster, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Zeuschner
authors.affiliation: Faculty of Medicine, Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine and University of Münster, D-48149 Münster, Germany.
authors.forename: M Gabriele
authors.initials: MG
authors.lastname: Bixel
authors.affiliation: VIB Vesalius Research Center, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Carlo
authors.initials: C
authors.lastname: Milia
authors.affiliation: Department of Nephrology and Hypertension, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Jaba
authors.initials: J
authors.lastname: Gamrekelashvili
authors.affiliation: Department of Plastic and Reconstructive Surgery, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Limbourg
authors.affiliation: Research group Ontogeny of Haematopoietic Stem Cells, MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, Scotland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Medvinsky
authors.affiliation: VIB Vesalius Research Center, KU Leuven, 3000 Leuven, Belgium.|Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
authors.forename: Massimo M
authors.initials: MM
authors.lastname: Santoro
authors.affiliation: Department of Nephrology and Hypertension, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Florian P
authors.initials: FP
authors.lastname: Limbourg
authors.affiliation: Faculty of Medicine, Department of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine and University of Münster, D-48149 Münster, Germany.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
mesh_terms: D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D001808:Blood Vessels / Q000254:growth & development; D001842:Bone and Bones / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology; D004164:Diphosphonates / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D051880:Receptors, Notch / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004164:Diphosphonates; D051880:Receptors, Notch; D019386:Alendronate