From the Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Spain (L.C., I.M.-P., C.B.-S., J.A., J.M.-G.).
CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain (L.C., I.M.-P., J.A., A.M.B., C.R., J.M.-G.).
Hypertension. 2021 Feb;77(2):557-570. doi: 10.1161/HYPERTENSIONAHA.120.16078. Epub 2020 Dec 28.
No drug therapy has shown to limit abdominal aortic aneurysm (AAA) growth or rupture, and the understanding of the disease biology is incomplete; whereby, one challenge of vascular medicine is the development of good animal models and therapies for this life-threatening condition. The nuclear receptor NOR-1 (neuron-derived orphan receptor 1) controls biological processes involved in AAA; however, whether it plays a role in this pathology is unknown. Through a gain-of-function approach we assessed the impact of NOR-1 expression on the vascular response to Ang II (angiotensin II). We used 2 mouse models that overexpress human NOR-1 in the vasculature, one of them specifically in vascular smooth muscle cells. NOR-1 transgenesis amplifies the response to Ang II enhancing vascular inflammation (production of proinflammatory cytokines, chemokines, and reactive oxygen species), increasing MMP (matrix metalloproteinase) activity and disturbing elastin integrity, thereby broking the resistance of C57BL/6 mice to Ang II-induced AAA. Genes encoding for proteins critically involved in AAA formation (, , , [C-X-C motif chemokine ligand 2], , and ) were upregulated in aneurysmal tissues. Both animal models show a similar incidence and severity of AAA, suggesting that high expression of NOR-1 in vascular smooth muscle cell is a sufficient condition to strengthen the response to Ang II. These alterations, including AAA formation, were prevented by the MMP inhibitor doxycycline. Microarray analysis identified gene sets that could explain the susceptibility of transgenic animals to Ang II-induced aneurysms, including those related with extracellular matrix remodeling, inflammatory/immune response, sympathetic activity, and vascular smooth muscle cell differentiation. These results involve NOR-1 in AAA and validate mice overexpressing this receptor as useful experimental models.
尚无药物疗法被证明可限制腹主动脉瘤（AAA）的生长或破裂，并且对该疾病的生物学理解尚不完全；因此，血管医学的一个挑战是为这种危及生命的疾病开发良好的动物模型和疗法。核受体 NOR-1（神经元衍生孤儿受体 1）控制与 AAA 相关的生物学过程；然而，它是否在这种病理中起作用尚不清楚。通过功能获得方法，我们评估了 NOR-1 表达对血管对 Ang II（血管紧张素 II）反应的影响。我们使用了两种在血管中过表达人 NOR-1 的小鼠模型，其中一种在血管平滑肌细胞中特异性过表达。NOR-1 转基因扩增了对 Ang II 的反应，增强了血管炎症（产生促炎细胞因子、趋化因子和活性氧），增加了 MMP（基质金属蛋白酶）活性并破坏了弹性蛋白的完整性，从而破坏了 C57BL/6 小鼠对 Ang II 诱导的 AAA 的抵抗。编码与 AAA 形成密切相关的蛋白质的基因（，，，[C-X-C 基序趋化因子配体 2]，，和）在动脉瘤组织中上调。两种动物模型均显示出相似的 AAA 发生率和严重程度，表明血管平滑肌细胞中 NOR-1 的高表达是增强对 Ang II 反应的充分条件。这些改变，包括 AAA 的形成，被 MMP 抑制剂强力霉素预防。基因表达谱分析确定了可以解释转基因动物对 Ang II 诱导的动脉瘤易感性的基因集，包括与细胞外基质重塑、炎症/免疫反应、交感神经活动和血管平滑肌细胞分化相关的基因集。这些结果将 NOR-1 与 AAA 联系起来，并验证了过表达该受体的小鼠作为有用的实验模型。
