Propranolol inhibits cavernous vascular malformations by [beta]1 adrenergic receptor antagonism in animal models

Introduction Cerebral cavernous malformations (CCMs) are vascular anomalies caused by mosaic inactivation of KRIT1 (also known as CCM1), CCM2, or PDCD10 (also known as CCM3) (1). We recently used CRISPR/Cas9 [...]
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 p antagonism, had no effect. Silencing of the [beta]1, but not p2, 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 Pdcd10/Ccm3 form of CCM. Propranolol or other [beta]1-selective antagonists may be beneficial in CCM disease.