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Full-length Dhh and N-terminal Shh act as competitive antagonists to regulate angiogenesis and vascular permeability.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2021 Nov 01; Vol. 117 (12), pp. 2489-2501. - Publication Year :
- 2021
-
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.<br />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.<br />Conclusion: The present study highlights for the first time that FL-Dhh and N-Hh ligands have antagonistic properties especially in ECs.<br /> (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 117
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 33063110
- Full Text :
- https://doi.org/10.1093/cvr/cvaa285