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

Propranolol, a pleiotropic beta-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 beta antagonism, had no effect. Silencing of the beta 1 but not beta 2, adrenergic receptor mimicked the beneficial effects of propranolol in a zebrafish CCM model, as did the beta 1-selective antagonist metoprolol. Thus, propranolol ameliorated cavernous malformations by beta 1 adrenergic antagonism in zebrafish. Oral propranolol significantly reduced lesion burden in 2 chronic murine models of the exceptionally aggressive Pdcd/Ccm3 form of CCM. Propranolol or other beta 1-selective antagonists may be beneficial in CCM disease.

Automated summary

Propranolol, a pleiotropic beta-adrenergic blocker, has shown promising results in reducing cerebral cavernous malformations in animal models such as zebrafish and mice, possibly due to its beta 1 adrenergic antagonism. These findings suggest that propranolol or other beta 1-selective antagonists may be beneficial in treating CCM disease.