Abstract: Changes in the nerve's microenvironment and local inflammation resulting from peripheral nerve injury participate in nerve sensitization and neuropathic pain development. Taking part in these early changes, disruption of the blood–nerve barrier (BNB) allows for infiltration of immunocytes and promotes the neuroinflammation. However, molecular mechanisms engaged in vascular endothelial cells (VEC) dysfunction and BNB alterations remain unclear. In vivo, BNB permeability was assessed following chronic constriction injury (CCI) of the rat sciatic nerve (ScN) and differential expression of markers of VEC functional state, inflammation, and intracellular signaling was followed from 3 hours to 2 months postinjury. Several mechanisms potentially involved in functional alterations of VEC were evaluated in vitro using human VEC (hCMEC/D3), then confronted to in vivo physiopathological conditions. CCI of the ScN led to a rapid disruption of endoneurial vascular barrier that was correlated to a decreased production of endothelial tight-junction proteins and an early and sustained alteration of Hedgehog (Hh) signaling pathway. In vitro, activation of Toll-like receptor 4 in VEC downregulated the components of Hh pathway and altered the endothelial functional state. Inhibition of Hh signaling in the ScN of naive rats mimicked the biochemical and functional alterations observed after CCI and was, on its own, sufficient to evoke local neuroinflammation and sustained mechanical allodynia. Alteration of the Hh signaling pathway in VEC associated with peripheral nerve injury, is involved in BNB disruption and local inflammation, and could thus participate in the early changes leading to the peripheral nerve sensitization and, ultimately, neuropathic pain development.
Local blockade of Hedgehog signaling in rat sciatic nerve mimicked enhanced endoneurial vascular permeability, local neuroinflammation, and mechanical allodynia emergence typically evoked by nerve injury.
aUFR d'Odontologie, Université Paris Descartes, Hôpital Bretonneau, Paris, France
bCentre de Psychiatrie et Neurosciences, INSERM U894, Université Paris Descartes, Hôpital Sainte-Anne, Paris, France
cUniversité Paris Descartes, Institut Cochin, Paris, France
dDepartment of Biological Sciences, The Open University, Walton Hall, Milton Keynes, United Kingdom
eWeill Medical College of Cornell University, New York, NY, USA
fUFR d'Odontologie, Université Paris Diderot, Hôpital Pitié Salpêtrière, Paris, France
Corresponding author. Address: UFR d'Odontologie, Université Paris Diderot, 5 rue garanciere, Paris 75006, France. Tel.: 0033695619036. E-mail address: firstname.lastname@example.org (Y. Boucher).
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Received June 28, 2015
Received November 04, 2015
Accepted November 20, 2015