Cardiovascular Institute and Department of Medicine, Perelman School of Medicine (L.L., A.A.R., S.G., J.Y., J.B., P.M.-I., J.G., M.L.K.), University of Pennsylvania, Philadelphia.
Department of Neurosurgery, Perelman School of Medicine, Hospital of the University of Pennsylvania (L.L., Y.S.S., J.-K.B.), University of Pennsylvania, Philadelphia.
Stroke. 2023 Nov;54(11):2906-2917. doi: 10.1161/STROKEAHA.123.044108. Epub 2023 Sep 25.
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 (encoding the enzymatic subunit of the PI3K (phosphoinositide 3-kinase) pathway associated with cell growth) synergize with CCM gene loss-of-function to generate rapidly growing lesions.
We recently developed a model of CCM formation that closely reproduces key events in human CCM formation through inducible CCM loss-of-function and gain-of-function in mature mice. In the present study, we use this model to test the ability of rapamycin, a clinically approved inhibitor of the PI3K effector mTORC1, to treat rapidly growing CCMs.
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.
脑静脉畸形（CCMs）是一种常见的血管畸形，常导致中风。CCMs 是由于编码 CCM 复合物的基因之一失去功能引起的，CCM 复合物是血管内皮细胞中 MEKK3-KLF2/4 信号的负调节剂。PI3K（磷脂酰肌醇 3-激酶）途径与细胞生长相关的编码酶亚基的 （PI3K 途径编码酶亚基）获得性功能突变与 CCM 基因失活协同作用，导致快速生长的病变。
我们最近开发了一种 CCM 形成模型，通过成熟小鼠中的诱导性 CCM 失活和获得性功能，很好地模拟了人类 CCM 形成中的关键事件。在本研究中，我们使用该模型来测试雷帕霉素（一种临床批准的 PI3K 效应物 mTORC1 的抑制剂）治疗快速生长的 CCM 的能力。
我们表明，雷帕霉素的腹腔内和口服给药均可阻止 CCM 的生长，减少病变周围铁沉积，并改善 CCM 内的血管灌注。
我们的发现进一步确立了这种成年 CCM 模型作为一种有价值的临床前模型，并支持临床测试雷帕霉素治疗快速生长的人类 CCM。
