title: Impaired Hedgehog signalling-induced endothelial dysfunction is sufficient to induce neuropathy: implication in diabetes.
abstract: OBJECTIVE
  Microangiopathy, i.e. endothelial dysfunction, has long been suggested to contribute to the development of diabetic neuropathy, although this has never been fully verified. In the present paper, we have identified the role of Hedgehog (Hh) signalling in endoneurial microvessel integrity and evaluated the impact of impaired Hh signalling in endothelial cells (ECs) on nerve function.
  
  
  RESULTS
  By using Desert Hedgehog (Dhh)-deficient mice, we have revealed, that in the absence of Dhh, endoneurial capillaries are abnormally dense and permeable. Furthermore, Smoothened (Smo) conditional KO mice clarified that this increased vessel permeability is specifically due to impaired Hh signalling in ECs and is associated with a down-regulation of Claudin5 (Cldn5). Moreover, impairment of Hh signalling in ECs was sufficient to induce hypoalgesia and neuropathic pain. Finally in Lepr(db/db) type 2 diabetic mice, the loss of Dhh expression observed in the nerve was shown to be associated with increased endoneurial capillary permeability and decreased Cldn5 expression. Conversely, systemic administration of the Smo agonist SAG increased Cldn5 expression, decreased endoneurial capillary permeability, and restored thermal algesia to diabetic mice, demonstrating that loss of Dhh expression is crucial in the development of diabetic neuropathy.
  
  
  CONCLUSIONS
  The present work demonstrates the critical role of Dhh in maintaining blood nerve barrier integrity and demonstrates for the first time that endothelial dysfunction is sufficient to induce neuropathy.
authors.affiliation: Université de Bordeaux, Adaptation Cardiovasculaire à L'ischémie, U1034, Pessac F-33600, France INSERM, U1034, Adaptation Cardiovasculaire à L'ischémie, 1, Avenue de Magellan, Pessac F-33600, France CHU de Bordeaux, Pharmacie de L'hôpital Haut Lévêque, Pessac F-33600, France.
authors.forename: Candice
authors.initials: C
authors.lastname: Chapouly
authors.affiliation: Université de Bordeaux, Adaptation Cardiovasculaire à L'ischémie, U1034, Pessac F-33600, France INSERM, U1034, Adaptation Cardiovasculaire à L'ischémie, 1, Avenue de Magellan, Pessac F-33600, France.
authors.forename: Qinyu
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Université de Bordeaux, Adaptation Cardiovasculaire à L'ischémie, U1034, Pessac F-33600, France INSERM, U1034, Adaptation Cardiovasculaire à L'ischémie, 1, Avenue de Magellan, Pessac F-33600, France CHU de Bordeaux, Pharmacie de L'hôpital Haut Lévêque, Pessac F-33600, France.
authors.forename: Soizic
authors.initials: S
authors.lastname: Vandierdonck
authors.affiliation: Université de Bordeaux, Adaptation Cardiovasculaire à L'ischémie, U1034, Pessac F-33600, France INSERM, U1034, Adaptation Cardiovasculaire à L'ischémie, 1, Avenue de Magellan, Pessac F-33600, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Larrieu-Lahargue
authors.affiliation: Department of Neurology, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: Mariani
authors.affiliation: Université de Bordeaux, Adaptation Cardiovasculaire à L'ischémie, U1034, Pessac F-33600, France INSERM, U1034, Adaptation Cardiovasculaire à L'ischémie, 1, Avenue de Magellan, Pessac F-33600, France.
authors.forename: Alain-Pierre
authors.initials: AP
authors.lastname: Gadeau
authors.affiliation: Université de Bordeaux, Adaptation Cardiovasculaire à L'ischémie, U1034, Pessac F-33600, France INSERM, U1034, Adaptation Cardiovasculaire à L'ischémie, 1, Avenue de Magellan, Pessac F-33600, France marie-ange.renault@inserm.fr.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Renault
mesh_terms: D000818:Animals; D002196:Capillaries / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism*; D004727:Endothelium / Q000503:physiopathology*; D053823:Hedgehog Proteins / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology; D000072086:Smoothened Receptor / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; C491022:Smo protein, mouse; D000072086:Smoothened Receptor
keywords: Blood nerve barrier; Desert hedgehog; Diabetic neuropathy; Permeability