Rapamycin Partially Reverts Cavernoma Endothelial Cell Phenotype and, When Combined With Lapatinib, Ameliorates...

This study investigates the impact of rapamycin and propranolol on cerebral cavernous malformations (CCMs). Employing an unbiased transcriptomic analysis, we aimed to comprehensively elucidate the molecular mechanisms underlying these drug effects. Mouse Brain Microvascular Endothelial Cells (mBMEC) deficient in Ccm3 were treated with propranolol or rapamycin and were analysed by RNA-seq and immunofluorescence. While propranolol shows limited efficacy in modulating the CCM transcriptomic phenotype in mBMEC, rapamycin demonstrates a significant impact. Rapamycin partially reverses gene expression changes induced by Ccm3 deficiency, restoring KLF2/4-dependent genes like Nos3, Adamts1, and Thbs1. Notably, we observed a reduction in KLF2 protein levels in Ccm3 KO cells treated with rapamycin. We also sought to determine whether rapamycin, especially in combination with the tyrosine kinase inhibitor lapatinib, which induces proapoptotic gene expression in Ccm3-deficient endothelium, can reduce lesion volume even after lesion growth has occurred. Ccm3^iEC mice in which cavernoma development had been induced were treated with rapamycin alone or combined with lapatinib, assessing lesion volume using micro-CT imaging. Notably, a combination of rapamycin and lapatinib effectively reduces lesion volume in a chronic CCM model. In summary, our work reveals a mechanism by which rapamycin modulates Ccm3 KO endothelial cells and identifies rapamycin plus lapatinib as a possible combination therapy for cavernomas.