Aims

Aorta exhibits regional heterogeneity (structural and functional), while different etiologies for thoracic and abdominal aortic aneurysm (TAA, AAA) are recognized. Tissue inhibitor of metalloproteinases (TIMPs) regulate vascular remodeling through different mechanisms. Region-dependent functions have been reported for TIMP3 and TIMP4 in vascular pathologies. We investigated the region-specific function of these TIMPs in development of TAA versus AAA.

Methods & results

TAA or AAA was induced in male and female mice lacking TIMP3 (Timp3^−/−), TIMP4 (Timp4^−/−) or in wildtype (WT) mice by peri-adventitial elastase application. Loss of TIMP3 exacerbated TAA and AAA severity in males and females, with a greater increase in proteinase activity, smooth muscle cell phenotypic switching post-AAA and -TAA, while increased inflammation was detected in the media post-AAA, but in the adventitia post-TAA. Timp3^−/− mice showed impaired intimal barrier integrity post-AAA, but a greater adventitial vasa-vasorum branching post-TAA, which could explain the site of inflammation in AAA versus TAA. Severity of TAA and AAA in Timp4^−/− mice was similar to WT mice. In vitro, Timp3 knockdown more severely compromised the permeability of human aortic EC monolayer compared to Timp4 knockdown or the control group. In aneurysmal aorta specimens from patients, TIMP3 expression decreased in the media in AAA, and in adventitial in TAA specimens, consistent with the impact of its loss in AAA versus TAA in mice.

Conclusion

TIMP3 loss exacerbates inflammation, adverse remodeling and aortic dilation, but triggers different patterns of remodeling in AAA versus TAA, and through different mechanisms.

中文翻译：

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TIMP3 的缺失而非 TIMP4 的缺失会加剧胸主动脉瘤和腹​​主动脉瘤

目标

主动脉表现出区域异质性（结构和功能），而胸主动脉瘤和腹​​主动脉瘤（TAA、AAA）的病因不同。金属蛋白酶组织抑制剂（TIMP）通过不同的机制调节血管重塑。据报道，TIMP3 和 TIMP4 在血管病理学中具有区域依赖性功能。我们研究了这些 TIMP 在 TAA 与 AAA 发展中的区域特异性功能。

方法与结果

通过应用外膜周围弹性蛋白酶，在缺乏 TIMP3 ( Timp3 ^−/− )、TIMP4 ( Timp4 ^−/− )的雄性和雌性小鼠或野生型 (WT) 小鼠中诱导 TAA 或 AAA 。TIMP3的缺失加剧了男性和女性TAA和AAA的严重程度，AAA和-TAA后蛋白酶活性、平滑肌细胞表型转换更大程度增加，同时在AAA后中膜中检测到炎症增加，但在AAA后外膜中发现炎症增加-TAA。Timp3 ^-/−小鼠在 AAA 后表现出内膜屏障完整性受损，但在 TAA 后外膜血管滋养管分支更大，这可以解释 AAA 与 TAA 中的炎症部位。Timp4 ^-/−小鼠中 TAA 和 AAA 的严重程度与 WT 小鼠相似。在体外，与Timp4敲除或对照组相比， Timp3敲除更严重地损害了人主动脉 EC 单层的通透性。在患者的动脉瘤主动脉标本中，TIMP3 在 AAA 中膜和 TAA 标本中外膜中表达降低，这与 AAA 与小鼠 TAA 中 TIMP3 缺失的影响一致。

结论

TIMP3 缺失会加剧炎症、不良重塑和主动脉扩张，但会通过不同机制触发 AAA 与 TAA 不同的重塑模式。