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Full-length dhh and N-terminal shh act as competitive antagonists to regulate angiogenesis and vascular permeability

Abstract : 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. Aims: The purpose of the present paper is to clarify some conflicting literature data. Methods and results: : With this goal we have demonstrated that, unexpectedly, ectopically administered N-terminal Sonic Hedgehog (N-Shh) and endogenous endothelial-derived Desert Hedgehog (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 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 Patched-1, they induce distinct Patched-1 localization. Finally, we confirmed that in a pathophysiological setting i.e. brain inflammation, astrocyte-derived N-Shh act 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. Translational perspective: As a consequence, Hh ligands or forms of Hh ligands cannot be used instead of another for therapeutic purposes.
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https://www.hal.inserm.fr/inserm-02983027
Contributor : Christelle Boullé <>
Submitted on : Thursday, October 29, 2020 - 11:14:01 AM
Last modification on : Thursday, February 25, 2021 - 11:27:47 AM
Long-term archiving on: : Saturday, January 30, 2021 - 6:14:51 PM

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Pierre-Louis Hollier, Candice Chapouly, Aissata Diop, Sarah Guimbal, Lauriane Cornuault, et al.. Full-length dhh and N-terminal shh act as competitive antagonists to regulate angiogenesis and vascular permeability. Cardiovascular Research, Oxford University Press (OUP), 2020, cvaa285, Online ahead of print. ⟨10.1093/cvr/cvaa285⟩. ⟨inserm-02983027⟩

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