1. Could an endoneurial endothelial crosstalk between Wnt/β-catenin and Sonic Hedgehog pathways underlie the early disruption of the infra-orbital blood-nerve barrier following chronic constriction injury?
- Author
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Moreau, Nathan, Mauborgne, Annie, Couraud, Pierre-Olivier, Romero, Ignacio A, Weksler, Babette B, Villanueva, Luis, Pohl, Michel, Boucher, Yves, Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Life, Health and Chemical Sciences, The Open University [Milton Keynes] (OU), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 - UFR Odontologie (UPD7 Odontologie), Université Paris Diderot - Paris 7 (UPD7), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Boucher, Yves, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Odontologie [Bretonneau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bretonneau, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Weill Medical College of Cornell University [New York], HAL UPMC, Gestionnaire, Centre de Psychiatrie et Neurosciences (CPN - U894), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Bretonneau, Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [APHP], and Université Paris Diderot - Paris 7 - UFR Odontologie (UPD7 UFR Odontologie)
- Subjects
Male ,tight junctions ,animal structures ,MESH: pain ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,toll-like receptor 4 ,MESH: endothelial cell ,Constriction, Pathologic ,b-catenin ,Neuropathic pain ,Rats, Sprague-Dawley ,Wnt ,Peripheral Nerve Injuries ,Animals ,Hedgehog Proteins ,rat ,Wnt Signaling Pathway ,vascular permeability ,beta Catenin ,Blood-Nerve Barrier ,Pain and nociception ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,MESH: neurovascular unit ,β-catenin ,MESH: beta catenin ,endothelial cells ,Sonic Hedgehog ,MESH: rat ,MESH: neuropathic ,Chronic Disease ,Neuralgia ,Neurovascular unit NVU ,MESH: Wnt ,Research Article - Abstract
BackgroundBlood–nerve barrier disruption is pivotal in the development of neuroinflammation, peripheral sensitization, and neuropathic pain after peripheral nerve injury. Activation of toll-like receptor 4 and inactivation of Sonic Hedgehog signaling pathways within the endoneurial endothelial cells are key events, resulting in the infiltration of harmful molecules and immunocytes within the nerve parenchyma. However, we showed in a previous study that preemptive inactivation of toll-like receptor 4 signaling or sustained activation of Sonic Hedgehog signaling did not prevent the local alterations observed following peripheral nerve injury, suggesting the implication of another signaling pathway.MethodsUsing a classical neuropathic pain model, the infraorbital nerve chronic constriction injury (IoN-CCI), we investigated the role of the Wnt/β-catenin pathway in chronic constriction injury-mediated blood–nerve barrier disruption and in its interactions with the toll-like receptor 4 and Sonic Hedgehog pathways. In the IoN-CCI model versus control, mRNA expression levels and/or immunochemical detection of major Wnt/Sonic Hedgehog pathway (Frizzled-7, vascular endothelial-cadherin, Patched-1 and Gli-1) and/or tight junction proteins (Claudin-1, Claudin-5, and Occludin) readouts were assessed. Vascular permeability was assessed by sodium fluorescein extravasation.ResultsIoN-CCI induced early alterations in the vascular endothelial-cadherin/β-catenin/Frizzled-7 complex, shown to participate in local blood–nerve barrier disruption via a β-catenin-dependent tight junction protein downregulation. Wnt pathway also mediated a crosstalk between toll-like receptor 4 and Sonic Hedgehog signaling within endoneurial endothelial cells. Nevertheless, preemptive inhibition of Wnt/β-catenin signaling before IoN-CCI could not prevent the downregulation of key Sonic Hedgehog pathway readouts or the disruption of the infraorbital blood–nerve barrier, suggesting that Sonic Hedgehog pathway inhibition observed following IoN-CCI is an independent event responsible for blood–nerve barrier disruption.ConclusionA crosstalk between Wnt/β-catenin- and Sonic Hedgehog-mediated signaling pathways within endoneurial endothelial cells could mediate the chronic disruption of the blood–nerve barrier following IoN-CCI, resulting in increased irreversible endoneurial vascular permeability and neuropathic pain development.
- Published
- 2017
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