PUBLICATION
Internal modulation of proteolysis in vascular extracellular matrix remodeling: role of ADAM metallopeptidase with thrombospondin type 1 motif 5 in the development of intracranial aneurysm rupture
- Authors
- Wang, W., Zhang, H., Hou, C., Liu, Q., Yang, S., Zhang, Z., Yang, W., Yang, X.
- ID
- ZDB-PUB-210504-4
- Date
- 2021
- Source
- Aging 13(9): 12800-12816 (Journal)
- Registered Authors
- Keywords
- ADAMTS-5, animal model, extracellular matrix, intracranial aneurysm
- MeSH Terms
-
- ADAMTS5 Protein/administration & dosage
- ADAMTS5 Protein/genetics
- ADAMTS5 Protein/metabolism*
- Adult
- Aged
- Animals
- Disease Models, Animal
- Embryo, Nonmammalian
- Extracellular Matrix/pathology*
- Female
- Humans
- Injections, Intraperitoneal
- Intracranial Aneurysm/complications*
- Intracranial Aneurysm/drug therapy
- Intracranial Aneurysm/pathology
- Intracranial Aneurysm/surgery
- Male
- Mice
- Proteolysis
- Recombinant Proteins/administration & dosage
- Rupture, Spontaneous/etiology
- Rupture, Spontaneous/pathology
- Rupture, Spontaneous/prevention & control
- Vascular Remodeling
- Zebrafish
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/metabolism
- PubMed
- 33934089 Full text @ Aging (Albany NY)
Citation
Wang, W., Zhang, H., Hou, C., Liu, Q., Yang, S., Zhang, Z., Yang, W., Yang, X. (2021) Internal modulation of proteolysis in vascular extracellular matrix remodeling: role of ADAM metallopeptidase with thrombospondin type 1 motif 5 in the development of intracranial aneurysm rupture. Aging. 13(9):12800-12816.
Abstract
Intracranial aneurysms (IAs) are common cerebrovascular diseases that carry a high mortality rate, and the mechanisms that contribute to IA formation and rupture have not been elucidated. ADAMTS-5 (ADAM Metallopeptidase with Thrombospondin Type 1 Motif 5) is a secreted proteinase involved in matrix degradation and ECM (extracellular matrix) remodeling processes, and we hypothesized that the dysregulation of ADAMTS-5 could play a role in the pathophysiology of IA. Immunofluorescence revealed that the ADAMTS-5 levels were decreased in human and murine IA samples. The administration of recombinant protein ADAMTS-5 significantly reduced the incidence of aneurysm rupture in the experimental model of IA. IA artery tissue was collected and utilized for histology, immunostaining, and specific gene expression analysis. Additionally, the IA arteries in ADAMTS-5-administered mice showed reduced elastic fiber destruction, proteoglycan accumulation, macrophage infiltration, inflammatory response, and apoptosis. To further verify the role of ADAMTS-5 in cerebral vessels, a specific ADAMTS-5 inhibitor was used on another model animal, zebrafish, and intracranial hemorrhage was observed in zebrafish embryos. In conclusion, our findings indicate that ADAMTS-5 is downregulated in human IA, and compensatory ADAMTS-5 administration inhibits IA development and rupture with potentially important implications for treating this cerebrovascular disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping