腹主动脉瘤在老年人中发病率高、死亡率高。一直以来认为平滑肌层诱导的炎症反应和动脉内膜中层弹性纤维的降解是腹主动脉瘤形成主因，而内皮的作用不明并被长期忽视。我们前期的研究显示血管紧张素II（AngII）能诱导hph1老鼠内皮一氧化氮合成酶（eNOS）解耦联而导致腹主动脉瘤。hph1老鼠有三磷酸鸟苷环水解酶（GCH1）变异导致的四氢生物蝶呤（BH4）合成缺陷，而BH4是eNOS的辅酶，其缺乏可致eNOS解耦联。同时，其他组也证实内皮细胞上血管紧张素II受体介导了动脉瘤的形成。因此内皮特别是GCH1在动脉瘤形成中的作用需要重新认识。本课题利用体外机械力装置和内皮特异性GCH1基因敲除鼠建立两种不同的动脉瘤模型探讨内皮GCH1与动脉瘤其他致病因素的相互关系，继续阐明内皮以及GCH1缺陷所致的eNOS解耦联在腹主动脉瘤形成中的作用，为腹主动脉瘤的辅助性内科治疗提供理论基础和新思路。

Abstract: Abdominal aortic aneurysm (AAA) has a high morbidity and mortality in the elderly. Previously, the degradation of media elastic fibers in aortic intima and inflammation induced in smooth muscle layer was considered the main causes for AAA. The role of endothelium is unknown and however neglected. Our preliminary studies indicated that Angiotensin II (AngII) can induce AAA formation in hph1 mouse via endothelial nitric oxide synthase (eNOS) uncoupling.The hph1 mouse is a mouse model associated with GTP cyclohydrolase (GCH1) mutagenesis which leads to tetrahydrobiopterin (BH4) deficiency and eNOS uncoupling.Moreover, another group also demonstrated that endothelial Angiotensin II receptor mediated the AAA formation. Therefore, the role of endothelium,especially eNOS uncoupling in AAA formation need to be re-evaluated. In this study, an in vitro mechanical stress device and two different AAA models developed from conditional endothelial specific GCH1 knockout mice are used to examine the role of endothelial specific GCH1 in AAA formation and the interaction between GCH1 knockout，eNOS uncoupling and other pathological factors in AAA development are also investigated. The GCH1 silencing is retrieved to assess its therapeutic effect on AAA incident and other causal factors. For the first time we are able to illustrate the critical role of endothelial GCH1 knockout and the consequent eNOS uncoupling in the pathogenesis of AAA and a novel treatment target for intervention is proposed.