1. Full-length Dhh and N-terminal Shh act as competitive antagonists to regulate angiogenesis and vascular permeability.
- Author
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Hollier PL, Chapouly C, Diop A, Guimbal S, Cornuault L, Gadeau AP, and Renault MA
- Subjects
- Animals, Astrocytes drug effects, Astrocytes pathology, Cells, Cultured, Corneal Neovascularization genetics, Corneal Neovascularization pathology, Encephalomyelitis, Autoimmune, Experimental genetics, Encephalomyelitis, Autoimmune, Experimental pathology, Endothelial Cells drug effects, Endothelial Cells pathology, Female, Hedgehog Proteins administration & dosage, Hedgehog Proteins genetics, Ligands, Male, Mice, Knockout, Patched-1 Receptor metabolism, Protein Binding, Signal Transduction, Smoothened Receptor genetics, Smoothened Receptor metabolism, Mice, Astrocytes metabolism, Capillary Permeability drug effects, Cerebral Cortex blood supply, Corneal Neovascularization metabolism, Encephalomyelitis, Autoimmune, Experimental metabolism, Endothelial Cells metabolism, Hedgehog Proteins metabolism, Neovascularization, Pathologic
- 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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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