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

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

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 1

Propranolol and S-(-)-propranolol, but not R-(+)-propranolol, rescues embryonic CVP dilation in ccm2 CRISPR embryos.

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Propranolol and S-(-)-propranolol, but not R-(+)-propranolol, rescues em...
At the 1-cell stage, Tg(fli1:EGFP; gata1:DsRED) embryos, expressing EGFP in endothelial cells and DsRED in red blood cells, were injected with cas9 mRNA and gRNAs targeting ccm2. At 24 hpf, the ccm2 CRISPR embryos were treated with 100 μM propranolol, S-(-)-propranolol, or R-(+)-propranolol. The CVP was scanned at 30 hpf (A–D), 36 hpf (E–H), and 2 days post fertilization (dpf) (I–L). Whereas R-(+)-propranolol–treated (C, G, and K) and untreated CRISPR embryos (D, H, and L) displayed abnormal intussusceptions within the dorsal vein and lack of a ventral vein, racemic propranolol–treated (A, E, and I) and S-(-)-propranolol–treated (B, F, and J) CRISPR embryos formed the primitive venous plexus by 30 hpf (A and B), a normal functional ventral vein by 36 hpf (E and F), and a mature caudal venous plexus by 2 dpf (I and J). Arrows indicate intussusceptions. Blue and yellow bars indicate the dorsal and ventral veins, respectively. The embryos shown in A–T are in the sagittal plane. Bright-field images revealed normal CVP development of racemic propranolol–treated (M) and S-(-)-propranolol–treated CRISPR embryos (N), whereas approximately 30% of R-(+)-propranolol–treated (O) and untreated (control) ccm2 CRISPR embryos (P) had dramatic CVP dilation. Approximately 10% of embryos in all 4 groups showed heart dilation (Q–T). Scale bars: 50 μm (A–L), 500 μm (M–P), and 200 μm (Q–T). Quantitation of ccm2 CRISPR embryos with cardiovascular defects (U) revealed that, compared with the untreated controls, significantly fewer propranolol-treated embryos harbored CVP dilation (****P < 0.0001), whereas a similar proportion exhibited heart dilation (P = 0.11). Quantitation of ccm2 CRISPR embryos with CVP dilation (V) showed that the S-(-)-propranolol enantiomer rescued CVP dilation (*P = 0.036), whereas the R-(+)-propranlol enantiomer failed to do so (P = 1.0) compared with untreated control embryos. A 2-tailed Fisher exact test was used for comparisons. Each replicate (colored bars) is presented with the total number. Black bars indicate the mean in U.