Université Joseph Fourier, Grenoble, F-38041, France.
J Pathol. 2011 May;224(1):33-44. doi: 10.1002/path.2840. Epub 2011 Mar 22.
Fibrillin-1, the major component of extracellular microfibrils that associate with insoluble elastin in elastic fibres, is mainly synthesized during development and postnatal growth and is believed to guide elastogenesis. Mutations in the fibrillin-1 gene cause Marfan syndrome, a multisystem disorder characterized by aortic aneurysms and dissections. The recent finding that early deficiency of elastin modifies vascular ageing has raised the possibility that fibrillin-1 deficiency could also contribute to late-onset pathology of vascular remodelling. To address this question, we examined cardiovascular function in 3-week-old, 6-month-old, and 24-month-old mice that are heterozygous for a hypomorphic structural mutation of fibrillin-1 (Fbn1{+/mgΔ} mice). Our results indicate that Fbn1{+/mgΔ} mice, particularly those that are 24 months old, are slightly more hypotensive than wild-type littermates. Additionally, aneurysm and aortic insufficiency were more frequently observed in ageing Fbn1{+/mgΔ}$ mice than in the wild-type counterparts. We also noted substantial fragmentation and decreased number of elastic lamellae in the aortic wall of Fbn1{+/mgΔ} mice, which were correlated with an increase in aortic stiffness, a decrease in vasoreactivity, altered expression of elastic fibre-related genes, including fibrillin-1 and elastin, and a decrease in the relative ratio between tissue elastin and collagen. Collectively, our findings suggest that the heterozygous mgΔ mutation accelerates some aspects of vascular ageing and eventually leads to aortic manifestations resembling those of Marfan syndrome. Importantly, our data also indicate that vascular abnormalities in Fbn1{+/mgΔ} mice are opposite to those induced by elastin haploinsufficiency during ageing that affect blood pressure, vascular dimensions, and number of elastic lamellae.
原纤维蛋白 1 是细胞外微纤维的主要成分,与弹性纤维中的不溶性弹性蛋白结合,主要在发育和出生后生长过程中合成,被认为可以指导弹性蛋白的生成。原纤维蛋白 1 基因的突变会导致马凡综合征,这是一种多系统疾病,其特征是主动脉瘤和夹层。最近发现早期弹性蛋白缺乏会改变血管老化,这增加了原纤维蛋白 1 缺乏也可能导致血管重塑的晚期发病机制的可能性。为了回答这个问题,我们检查了杂合子结构突变原纤维蛋白 1 的 3 周龄、6 月龄和 24 月龄的小鼠的心血管功能(Fbn1{+/mgΔ} 小鼠)。我们的结果表明,Fbn1{+/mgΔ} 小鼠,尤其是 24 月龄的小鼠,比野生型同窝小鼠血压略低。此外,在衰老的 Fbn1{+/mgΔ}$ 小鼠中,更频繁地观察到动脉瘤和主动脉瓣关闭不全。我们还注意到 Fbn1{+/mgΔ} 小鼠的主动脉壁弹性小体明显碎裂和数量减少,这与主动脉僵硬度增加、血管反应性降低、弹性纤维相关基因表达改变(包括原纤维蛋白 1 和弹性蛋白)以及组织弹性蛋白与胶原的相对比例降低有关。总之,我们的研究结果表明,杂合子 mgΔ 突变加速了血管老化的某些方面,并最终导致类似于马凡综合征的主动脉表现。重要的是,我们的数据还表明,Fbn1{+/mgΔ} 小鼠的血管异常与衰老过程中弹性蛋白单倍不足引起的异常相反,影响血压、血管尺寸和弹性小体数量。