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Updated: May 15, 2026
Large Scale Zebrafish-Based In vivo Small Molecule Screen
Published on: December 30, 2010
Genetic inactivation of the β1 adrenergic receptor prevents cerebral cavernous malformations in zebrafish
Wenqing Li1, Sara McCurdy1, Miguel A Lopez-Ramirez1
1Department of Medicine, University of California, San Diego, San Diego, United States.
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.
Insights
The beta-1 adrenergic receptor (ADRB1) is crucial in cerebral cavernous malformations (CCMs). Blocking ADRB1 with propranolol or metoprolol significantly reduces CCM lesions in zebrafish, highlighting its therapeutic potential.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Pharmacology
Background:
- Cerebral cavernous malformations (CCMs) are vascular abnormalities.
- Previous studies indicated propranolol reduces CCMs and prevents embryonic caudal venous plexus (CVP) lesions.
- Morpholino silencing of the beta-1 adrenergic receptor (ADRB1) prevented embryonic CVP lesions, suggesting ADRB1's role.
Purpose of the Study:
- To investigate the role of ADRB1 in CCM pathogenesis.
- To determine if ADRB1 antagonism mediates the therapeutic effects of propranolol on CCMs.
Main Methods:
- Utilized zebrafish models with inactivated ccm2 to study CCMs and CVP lesions.
- Examined the effects of genetic knockout of ADRB1 in zebrafish.
- Administered beta-1 selective antagonists (propranolol, metoprolol) and a heart rate/contractility inhibitor (2,3-BDM).
- Assessed CVP lesion formation, CCM lesion volume, heart rate, contractility, and blood flow.
Main Results:
- Zebrafish lacking ADRB1 showed significantly fewer CVP lesions (86% reduction) and reduced CCM lesion volume (87% reduction).
- Metoprolol treatment mirrored propranolol's effect, reducing CCM lesion volume.
- ADRB1-deficient zebrafish exhibited reduced heart rate, contractility, and CVP blood flow.
- Inhibition of heart function and CVP blood flow with 2,3-BDM suppressed CVP lesions.
Conclusions:
- Genetic and pharmacological evidence supports ADRB1's critical role in CCM pathogenesis.
- The therapeutic effect of propranolol in CCMs is mediated through antagonism of the beta-1 adrenergic receptor.
- Targeting ADRB1 represents a potential therapeutic strategy for CCMs.
