Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of Radiology, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Radiology, Pediatric Imaging and Interventional Radiology, Children's Hospital of Wisconsin, Milwaukee, WI, USA.
Drug Discov Today. 2021 Aug;26(8):1790-1793. doi: 10.1016/j.drudis.2020.12.012. Epub 2020 Dec 24.
Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is a class of capillary anomalies that are associated with arteriovenous malformations and arteriovenous fistulas, which carry a risk of hemorrhages. There are no broadly effective pharmacological therapies currently available. Most CM-AVMs are associated with a loss of RASA1, resulting in constitutive activation of RAS signaling. However, protein interaction analysis revealed that RASA1 forms a complex with Rho GTPase-activating protein (RhoGAP), a negative regulator of RhoA signaling. Herein, we propose that loss of RASA1 function results in constitutive activation of RhoA signaling in endothelial cells, resulting in enhanced vascular permeability. Therefore, strategies aimed at curtailing RhoA activity should be tested as an adjunctive therapeutic approach in cell culture studies and animal models of RASA1 deficiency.
毛细血管畸形-动静脉畸形（CM-AVM）综合征是一类毛细血管异常，与动静脉畸形和动静脉瘘有关，存在出血风险。目前尚无广泛有效的药物治疗方法。大多数 CM-AVM 与 RASA1 的缺失有关，导致 RAS 信号的组成性激活。然而，蛋白质相互作用分析表明，RASA1 与 Rho GTP 酶激活蛋白（RhoGAP）形成复合物，后者是 RhoA 信号的负调节剂。在此，我们提出 RASA1 功能的丧失导致内皮细胞中 RhoA 信号的组成性激活，导致血管通透性增强。因此，在细胞培养研究和 RASA1 缺乏症的动物模型中，应测试旨在抑制 RhoA 活性的策略作为辅助治疗方法。
