sirolimus and Hemangioma--Cavernous--Central-Nervous-System

Cerebral cavernous malformations (CCMs) are vascular malformations that frequently cause stroke. CCMs arise due to loss of function in one of the genes that encode the CCM complex, a negative regulator of MEKK3-KLF2/4 signaling in vascular endothelial cells. Gain-of-function mutations in. We recently developed a model of CCM formation that closely reproduces key events in human CCM formation through inducible CCM loss-of-function and. We show that both intraperitoneal and oral administration of rapamycin arrests CCM growth, reduces perilesional iron deposition, and improves vascular perfusion within CCMs.. Our findings further establish this adult CCM model as a valuable preclinical model and support clinical testing of rapamycin to treat rapidly growing human CCMs.

Topics: Adult; Animals; Class I Phosphatidylinositol 3-Kinases; Endothelial Cells; Hemangioma, Cavernous, Central Nervous System; Humans; Mice; Phosphatidylinositol 3-Kinases; Sirolimus

Vascular malformations are thought to be monogenic disorders that result in dysregulated growth of blood vessels. In the brain, cerebral cavernous malformations (CCMs) arise owing to inactivation of the endothelial CCM protein complex, which is required to dampen the activity of the kinase MEKK3

Topics: Animals; Animals, Newborn; Class I Phosphatidylinositol 3-Kinases; Disease Models, Animal; Endothelial Cells; Gain of Function Mutation; Hemangioma, Cavernous, Central Nervous System; Humans; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Loss of Function Mutation; Male; MAP Kinase Kinase Kinase 3; Mechanistic Target of Rapamycin Complex 1; Mice; Mutation; Neoplasms; Sirolimus; TOR Serine-Threonine Kinases