PUBLICATION
Genetic inactivation of the β1 adrenergic receptor prevents cerebral cavernous malformations in zebrafish
- Authors
- Li, W., McCurdy, S., Lopez-Ramirez, M.A., Lee, H.S., Ginsberg, M.H.
- ID
- ZDB-PUB-250225-3
- Date
- 2025
- Source
- eLIFE 13: (Journal)
- Registered Authors
- Keywords
- beta1 adrenergic receptor, beta1 selective antagonist, cerebral cavernous malformation, developmental biology, vascular biology, zebrafish
- MeSH Terms
-
- Propranolol/pharmacology
- Receptors, Adrenergic, beta-1*/genetics
- Receptors, Adrenergic, beta-1*/metabolism
- Metoprolol/pharmacology
- Animals
- Zebrafish*/embryology
- Hemangioma, Cavernous, Central Nervous System*/drug therapy
- Hemangioma, Cavernous, Central Nervous System*/genetics
- Hemangioma, Cavernous, Central Nervous System*/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Heart Rate/drug effects
- Disease Models, Animal
- PubMed
- 39991834 Full text @ Elife
Citation
Li, W., McCurdy, S., Lopez-Ramirez, M.A., Lee, H.S., Ginsberg, M.H. (2025) Genetic inactivation of the β1 adrenergic receptor prevents cerebral cavernous malformations in zebrafish. eLIFE. 13:.
Abstract
Previously, we showed that propranolol reduces experimental murine cerebral cavernous malformations (CCMs) and prevents embryonic caudal venous plexus (CVP) lesions in zebrafish that follow mosaic inactivation of ccm2 (Li et al., 2021). Because morpholino silencing of the β1 adrenergic receptor (adrb1) prevents the embryonic CVP lesion, we proposed that adrb1 plays a role in CCM pathogenesis. Here, we report that adrb1-/- zebrafish exhibited 86% fewer CVP lesions and 87% reduction of CCM lesion volume relative to wild type brood mates at 2dpf and 8-10 weeks stage, respectively. Treatment with metoprolol, a β1 selective antagonist, yielded a similar reduction in CCM lesion volume. Adrb1-/- zebrafish embryos exhibited reduced heart rate and contractility and reduced CVP blood flow. Similarly, slowing the heart and eliminating the blood flow in CVP by administration of 2,3-BDM suppressed the CVP lesion. In sum, our findings provide genetic and pharmacological evidence that the therapeutic effect of propranolol on CCM is achieved through β1 receptor antagonism.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping