“…The research community has identified a number of different signaling pathways dysregulated following loss of the CCM genes: RhoA/ROCK [15][16][17][18], MEKK3-KLF2/4 [19][20][21], ICAP-1 and b1 integrin [22,23], DELTA-NOTCH [24], angiopoietin-2 [25], thrombomodulin and endothelial protein C receptor [26], reactive oxygen species (ROS) [27], autophagy [28], and endothelial-to-mesenchymal transition (EndMT) [29]. A nearly equal number of therapeutics have also been proposed or tested in CCM models: statins [15], fasudil [30], TGF-b inhibitors [29], sulindac [31], tempol [32], vitamin D3 [32], angiopoietin-2 neutralizing antibody [25], fluvastatin and zoledronate [33], indirubin-3'-monoxime [34], thrombospondin1 replacement [35], propranolol [36,37], ponatinib [38], BA1049 [39], and VEGFR2 inhibitor [40] . Several of these compounds arose from unbiased, highthroughput in vitro and in vivo screens of libraries containing thousands of compounds [32][33][34].…”