Kim Jungsil, Procknow Jesse D, Yanagisawa Hiromi, Wagenseil Jessica E
Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, Missouri;
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas; and Life Science Center of Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan.
Am J Physiol Heart Circ Physiol. 2015 Jul 1;309(1):H103-13. doi: 10.1152/ajpheart.00178.2015. Epub 2015 May 1.
Fibulin-4 is an extracellular matrix protein that is essential for proper assembly of arterial elastic fibers. Mutations in fibulin-4 cause cutis laxa with thoracic aortic aneurysms (TAAs). Sixty percent of TAAs occur in the ascending aorta (AA). Newborn mice lacking fibulin-4 (Fbln4(-/-)) have aneurysms in the AA, but narrowing in the descending aorta (DA), and are a unique model to investigate locational differences in aneurysm susceptibility. We measured mechanical behavior and gene expression of AA and DA segments in newborn Fbln4(-/-) and Fbln4(+/+) mice. Fbln4(-/-) AA has increased diameters compared with Fbln4(+/+) AA and Fbln4(-/-) DA at most applied pressures, confirming genotypic and locational specificity of the aneurysm phenotype. When diameter compliance and tangent modulus were calculated from the mechanical data, we found few significant differences between genotypes, suggesting that the mechanical response to incremental diameter changes is similar, despite the fragmented elastic fibers in Fbln4(-/-) aortas. Fbln4(-/-) aortas showed a trend toward increased circumferential stretch, which may be transmitted to smooth muscle cells (SMCs) in the wall. Gene expression data suggest activation of pathways for SMC proliferation and inflammation in Fbln4(-/-) aortas compared with Fbln4(+/+). Additional genes in both pathways, as well as matrix metalloprotease-8 (Mmp8), are upregulated specifically in Fbln4(-/-) AA compared with Fbln4(+/+) AA and Fbln4(-/-) DA. Mmp8 is a neutrophil collagenase that targets type 1 collagen, and upregulation may be necessary to allow diameter expansion in Fbln4(-/-) AA. Our results provide molecular and mechanical targets for further investigation in aneurysm pathogenesis.
纤连蛋白-4是一种细胞外基质蛋白，对动脉弹性纤维的正常组装至关重要。纤连蛋白-4的突变会导致皮肤松弛并伴有胸主动脉瘤（TAA）。60%的胸主动脉瘤发生在升主动脉（AA）。缺乏纤连蛋白-4（Fbln4(-/-)）的新生小鼠在升主动脉有动脉瘤，但降主动脉（DA）变窄，是研究动脉瘤易感性位置差异的独特模型。我们测量了新生Fbln4(-/-)和Fbln4(+/+)小鼠升主动脉和降主动脉节段的力学行为和基因表达。在大多数施加压力下，Fbln4(-/-)升主动脉的直径比Fbln4(+/+)升主动脉和Fbln4(-/-)降主动脉增大，证实了动脉瘤表型的基因型和位置特异性。当根据力学数据计算直径顺应性和切线模量时，我们发现基因型之间几乎没有显著差异，这表明尽管Fbln4(-/-)主动脉中的弹性纤维破碎，但对直径增量变化的力学反应相似。Fbln4(-/-)主动脉显示出圆周拉伸增加的趋势，这可能会传递到血管壁中的平滑肌细胞（SMC）。基因表达数据表明，与Fbln4(+/+)相比，Fbln4(-/-)主动脉中SMC增殖和炎症途径被激活。与Fbln4(+/+)升主动脉和Fbln4(-/-)降主动脉相比，这两条途径中的其他基因以及基质金属蛋白酶-8（Mmp8）在Fbln4(-/-)升主动脉中特异性上调。Mmp8是一种靶向I型胶原的中性粒细胞胶原酶，上调可能是Fbln4(-/-)升主动脉直径扩张所必需的。我们的结果为动脉瘤发病机制的进一步研究提供了分子和力学靶点。
