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Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism in animal models
Wenqing Li, … , Douglas A. Marchuk, Issam A. Awad
Wenqing Li, … , Douglas A. Marchuk, Issam A. Awad
Published December 10, 2020
Citation Information: J Clin Invest. 2021;131(3):e144893. https://doi.org/10.1172/JCI144893.
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Concise Communication Vascular biology Article has an altmetric score of 2

Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism in animal models

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Abstract

Propranolol, a pleiotropic β-adrenergic blocker, has been anecdotally reported to reduce cerebral cavernous malformations (CCMs) in humans. However, propranolol has not been rigorously evaluated in animal models, nor has its mechanism of action in CCM been defined. We report that propranolol or its S(-) enantiomer dramatically reduced embryonic venous cavernomas in ccm2 mosaic zebrafish, whereas R-(+)-propranolol, lacking β antagonism, had no effect. Silencing of the β1, but not β2, adrenergic receptor mimicked the beneficial effects of propranolol in a zebrafish CCM model, as did the β1-selective antagonist metoprolol. Thus, propranolol ameliorated cavernous malformations by β1 adrenergic antagonism in zebrafish. Oral propranolol significantly reduced lesion burden in 2 chronic murine models of the exceptionally aggressive Pdcd10/Ccm3 form of CCM. Propranolol or other β1-selective antagonists may be beneficial in CCM disease.

Authors

Wenqing Li, Robert Shenkar, Mathew R. Detter, Thomas Moore, Christian Benavides, Rhonda Lightle, Romuald Girard, Nicholas Hobson, Ying Cao, Yan Li, Erin Griffin, Carol Gallione, Joseph M. Zabramski, Mark H. Ginsberg, Douglas A. Marchuk, Issam A. Awad

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Figure 2

Loss of β1 adrenergic receptor function inhibits CVP dilation in ccm2 CRISPR embryos.

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Loss of β1 adrenergic receptor function inhibits CVP dilation in ccm2 CR...
(A) One-cell-stage embryos were coinjected with ccm2 CRISPR and an adrb1 morpholino (MO) (A and C) to silence the β1 receptor or with a control morpholino (B and C) and imaged at 48 hpf. (A) β1 Adrenergic receptor–silenced embryos formed a normal CVP, whereas control morpholino embryos (B) showed dramatic dilation. The blue bar indicates the lumen of the dorsal vein, and the yellow bar indicates the ventral vein. Scale bars: 50 μm. (C) Quantification of the embryos in replicate experiments showed that CVP dilation in ccm2 CRISPR embryos was reversed by silencing of the β1 adrenergic receptor with an adrb1–/– morpholino (****P < 0.0001), but not by silencing of the β2a adrenergic receptor with an adrb2a–/– morpholino (P = 0.89). (D) Specificity of β adrenergic antagonists. The β1-specific antagonist metoprolol (400 μM) was added 24 hpf, and embryos were imaged 48 hpf. Metoprolol reversed CVP dilation (*P = 0.018) in comparison with untreated control embryos. The fraction of defective embryos for each replicate experiment is indicated by colored bars (C and D). The mean of the values from replicate experiments is indicated by thin black lines (C). The numbers above the colored bars indicate the sample size for each replicate experiment in each group (C and D). A 2-tailed Fisher’s exact test was used for comparisons.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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