Affiliation:
1. Inserm, Biology of Cardiovascular Diseases, University of Bordeaux, U1034, 1, avenue de Magellan, F-33604 Pessac, France
Abstract
Abstract
Aims
The therapeutic potential of Hedgehog (Hh) signalling agonists for vascular diseases is of growing interest. However, molecular and cellular mechanisms underlying the role of the Hh signalling in vascular biology remain poorly understood. The purpose of the present article is to clarify some conflicting literature data.
Methods and results
With this goal, we have demonstrated that, unexpectedly, ectopically administered N-terminal Sonic Hh (N-Shh) and endogenous endothelial-derived Desert Hh (Dhh) induce opposite effects in endothelial cells (ECs). Notably, endothelial Dhh acts under its full-length soluble form (FL-Dhh) and activates Smoothened in ECs, while N-Shh inhibits it. At molecular level, N-Shh prevents FL-Dhh binding to Patched-1 (Ptch1) demonstrating that N-Shh acts as competitive antagonist to FL-Dhh. Besides, we found that even though FL-Hh ligands and N-Hh ligands all bind Ptch1, they induce distinct Ptch1 localization. Finally, we confirmed that in a pathophysiological setting, i.e. brain inflammation, astrocyte-derived N-Shh acts as a FL-Dhh antagonist.
Conclusion
The present study highlights for the first time that FL-Dhh and N-Hh ligands have antagonistic properties especially in ECs.
Funder
Fondation de France (Appel d’Offre Recherche sur les maladies Cardiovasculaires 2013
Fondation ARSEP pour la recherche sur la sclérose en plaques
Marie Skłodowska-Curie Actions
European council. Finally
Institut National de la Santé et de la Recherche Médicale
University of Bordeaux
Publisher
Oxford University Press (OUP)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
Cited by
5 articles.
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