Absence of LTBP-3 attenuates the aneurysmal phenotype but not spinal effects on the aorta in Marfan syndrome
Absence of LTBP-3 attenuates the aneurysmal phenotype but not spinal effects on the aorta in Marfan syndrome
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DOI：
10.1007/s10237-018-1080-1
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发表时间：
2019-02-01
影响因子：
3.5
通讯作者：
Bellini, C.
中科院分区：
文献类型：
--
作者：
Korneva, A.;Zilberberg, L.;Bellini, C.
纤颤素-1是一种与弹性蛋白相关的糖蛋白，有助于弹性纤维的长期抗疲劳性以及动脉中转化生长因子- β (TGF)的生物利用度。TGF生物利用度和/或信号的改变与马凡氏综合征（MFS）的动脉瘤发展有关，马凡氏综合征是一种由编码纤维蛋白1的基因突变引起的多系统疾病。我们最近发现，至少在12周龄的MFS小鼠中，纤维蛋白1缺陷小鼠中潜在转化生长因子- β结合蛋白3 （LTBP-3）的缺失减轻了弹性纤维的断裂和局灶性扩张，这是主动脉根动脉瘤的特征。本研究进一步表明，在MFS小鼠模型中，LTBP-3的缺失改善了胸主动脉的周向力学性能，这似乎是预防或显著延缓动脉瘤发展的基础。然而，在没有LTBP-3的情况下，脊柱畸形要么保留，要么加剧，似乎会对胸主动脉的轴向力学特性产生不利影响，从而降低整体血管功能，尽管没有动脉瘤扩张。重要的是，由于缺乏LTBP-3的小鼠体型较小，异速缩放有助于正确解释主动脉尺寸，从而促进临床表型。虽然本研究表明LTBP-3/TGF直接影响胸主动脉的生物力学功能，但它强调了MFS脊柱畸形可能间接地对主动脉整体表型产生不利影响。因此，有必要综合考虑这种综合征性疾病的血管和骨骼效应。
Fibrillin-1 is an elastin-associated glycoprotein that contributes to the long-term fatigue resistance of elastic fibers as well as to the bioavailability of transforming growth factor-beta (TGF) in arteries. Altered TGF bioavailability and/or signaling have been implicated in aneurysm development in Marfan syndrome (MFS), a multi-system condition resulting from mutations to the gene that encodes fibrillin-1. We recently showed that the absence of the latent transforming growth factor-beta binding protein-3 (LTBP-3) in fibrillin-1-deficient mice attenuates the fragmentation of elastic fibers and focal dilatations that are characteristic of aortic root aneurysms in MFS mice, at least to 12weeks of age. Here, we show further that the absence of LTBP-3 in this MFS mouse model improves the circumferential mechanical properties of the thoracic aorta, which appears to be fundamental in preventing or significantly delaying aneurysm development. Yet, a spinal deformity either remains or is exacerbated in the absence of LTBP-3 and seems to adversely affect the axial mechanical properties of the thoracic aorta, thus decreasing overall vascular function despite the absence of aneurysmal dilatation. Importantly, because of the smaller size of mice lacking LTBP-3, allometric scaling facilitates proper interpretation of aortic dimensions and thus the clinical phenotype. While this study demonstrates that LTBP-3/TGF directly affects the biomechanical function of the thoracic aorta, it highlights that spinal deformities in MFS might indirectly and adversely affect the overall aortic phenotype. There is a need, therefore, to consider together the vascular and skeletal effects in this syndromic disease.