GNAQ R183Q somatic mutation contributes to aberrant arteriovenous specification in Sturge-Weber syndrome through Notch signaling
GNAQ R183Q somatic mutation contributes to aberrant arteriovenous specification in Sturge-Weber syndrome through Notch signaling
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DOI：
10.1096/fj.202300608r
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发表时间：
2023-09-01
期刊：
影响因子：
4.8
通讯作者：
Guo，Wenyi
中科院分区：
文献类型：
--
作者：
Huang，Lulu;Sun，Hao;Guo，Wenyi
巩膜外血管畸形是Sturge-Weber综合征（SWS）继发性青光眼的重要特征，其密度和直径与眼压升高相关。我们以前报道过GNAQ R183 Q体细胞突变位于SWS巩膜外层。然而，GNAQ R183 Q导致巩膜外血管畸形的机制仍然知之甚少。在这项研究中，我们通过手术标本、人脐静脉内皮细胞（HUVEC）和HUVEC细胞系EA.hy926研究了GNAQ R183 Q和巩膜外血管畸形之间的相关性。我们的研究结果表明，巩膜外血管直径和GNAQ R183 Q变异体的频率之间呈正相关。此外，来自Notch信号通路的基因的上调以及动脉标志物EphrinB 2和静脉标志物EphB 4的异常共表达在SWS的巩膜脉管系统中得到证实。体外过表达GNAQ R183 Q的HUVEC的分析证实了Notch信号传导和动脉标志物的上调。此外，敲低Notch 1减少了GNAQ R183 Q诱导的动脉标志物的上调。我们的研究结果强烈表明，GNAQ R183 Q通过Notch诱导的异常动静脉特化导致巩膜外血管畸形。这些见解的分子基础上的巩膜血管畸形将提供新的途径，有效的治疗SWS继发性青光眼的发展。
Episcleral vasculature malformation is a significant feature of Sturge–Weber syndrome (SWS) secondary glaucoma, the density and diameter of which are correlated with increased intraocular pressure. We previously reported that the GNAQ R183Q somatic mutation was located in the SWS episclera. However, the mechanism by which GNAQ R183Q leads to episcleral vascular malformation remains poorly understood. In this study, we investigated the correlation between GNAQ R183Q and episcleral vascular malformation via surgical specimens, human umbilical vein endothelial cells (HUVECs), and the HUVEC cell line EA.hy926. Our findings demonstrated a positive correlation between episcleral vessel diameter and the frequency of the GNAQ R183Q variant. Furthermore, the upregulation of genes from the Notch signaling pathway and abnormal coexpression of the arterial marker EphrinB2 and venous marker EphB4 were demonstrated in the scleral vasculature of SWS. Analysis of HUVECs overexpressing GNAQ R183Q in vitro confirmed the upregulation of Notch signaling and arterial markers. In addition, knocking down of Notch1 diminished the upregulation of arterial markers induced by GNAQ R183Q. Our findings strongly suggest that GNAQ R183Q leads to malformed episcleral vasculatures through Notch‐induced aberrant arteriovenous specification. These insights into the molecular basis of episcleral vascular malformation will provide new pathways for the development of effective treatments for SWS secondary glaucoma.