Rapamycin can revert CCM phenotype in brain endothelial cells and ameliorates chronic cavernoma development in combination with lapatinib
Garcia-Colomer, M.; Martinez, J. E.; Diaz-Gomez, L.; Sartages, M.; Esquinas-Roman, E. M.; Riobello, C.; Martinez-Dalgado, D.; Gonzalez-Perez, D.; Gomez-Duran, A.; Fidalgo, M.; Varela-Rey, M.; Pombo, C. M.; Zalvide, J.
Show abstract
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 in Mouse Brain Microvascular Endothelial Cells (mBMEC) deficient in Ccm3. While propranolol shows limited efficacy in modulating the CCM transcriptomic phenotype in mBMEC, rapamycin demonstrates a higher impact. Rapamycin 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. Critically, in vivo experiments demonstrate that a combination of rapamycin and lapatinib effectively reduces lesion volume in a chronic CCM model. This finding is particularly noteworthy as it suggests a potential treatment strategy for existing lesions. In summary, our work describes a new mechanism for the effects of rapamycin in Ccm3- deficient cells and identifies a new drug combination in the treatment of cavernomas.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.