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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\n                    <jats:italic>Ccm3<\/jats:italic>\n                    were treated with propranolol or rapamycin and were analysed by RNA\u2010seq 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\n                    <jats:italic>Ccm3<\/jats:italic>\n                    deficiency, restoring KLF2\/4\u2010dependent genes like\n                    <jats:italic>Nos3<\/jats:italic>\n                    ,\n                    <jats:italic>Adamts1<\/jats:italic>\n                    , and\n                    <jats:italic>Thbs1<\/jats:italic>\n                    . Notably, we observed a reduction in KLF2 protein levels in\n                    <jats:italic>Ccm3<\/jats:italic>\n                    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\n                    <jats:italic>Ccm3<\/jats:italic>\n                    \u2010deficient endothelium, can reduce lesion volume even after lesion growth has occurred.\n                    <jats:italic>Ccm3<\/jats:italic>\n                    <jats:sup>iEC<\/jats:sup>\n                    mice in which cavernoma development had been induced were treated with rapamycin alone or combined with lapatinib, assessing lesion volume using micro\u2010CT 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\n                    <jats:italic>Ccm3<\/jats:italic>\n                    KO endothelial cells and identifies rapamycin plus lapatinib as a possible combination therapy for cavernomas.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.71280","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T06:50:47Z","timestamp":1783666247000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rapamycin Partially Reverts Cavernoma Endothelial Cell Phenotype and, When Combined With Lapatinib, Ameliorates Chronic Lesions"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4842-4016","authenticated-orcid":false,"given":"Mar","family":"Garc\u00eda\u2010Colomer","sequence":"first","affiliation":[{"name":"Department of Physiology, Centro Singular De Medicina Molecular E Enfermedades Cr\u00f3nicas 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