Dwivedi Krashn Kumar, Wu Yufan, Rother Jacob, Wagenseil Jessica E
Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO, United States.
Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO, United States.
Acta Biomater. 2025 Jun 15;200:218-235. doi: 10.1016/j.actbio.2025.05.056. Epub 2025 May 23.
Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the gene that encodes fibrillin-1, a glycoprotein necessary for elastic fiber assembly and stability in the large elastic arteries. MFS is associated with aortic aneurysms that typically occur in the proximal ascending aorta and have worse outcomes in males. Mechanisms for the sex- and region-specific differences in aneurysm development and outcomes are unknown. We quantified aortic geometry, microstructural remodeling, and passive biomechanics of the thoracic ascending, thoracic descending, abdominal suprarenal, and abdominal infrarenal aorta in 4 months old male and female Fbn1 (a model of severe MFS) and littermate wild-type mice to determine correlations between aortic geometry, microstructural remodeling, biomechanics, and aneurysmal dilation. We showed that aneurysmal dilation was strongly correlated with unloaded thickness, microstructural remodeling including loss of elastic fibers, deposition of collagen fibers, and decrease in cell nuclei number, and mechanical metrics including physiologic and ex vivo circumferential material stiffness. A multivariable mixed model showed that unloaded thickness, elastic fiber degradation, and ex vivo material stiffness predicted aneurysmal dilation with an adjusted R = 0.8818. Our results highlight the potential of geometric, microstructural remodeling, and biomechanical metrics to serve as physical biomarkers for personalized aortic aneurysm diagnosis and management in MFS. STATEMENT OF SIGNIFICANCE: Marfan syndrome (MFS) is a genetic disease associated with aortic aneurysms that have distinct sex- and region-specific outcomes. The mechanisms driving these variations are unclear. We used a severe MFS mouse model (Fbn1) to explore differences in microstructural remodeling and passive wall mechanics along the aortic length in males and females. We correlated these changes with aneurysm severity, as quantified by aortic dilation. We found that sex- and region-specific alterations in unloaded thickness, microstructural remodeling, and passive mechanical properties of the aortic wall play a critical role in aortic dilation. Our findings showed that mechanical metrics, particularly ex vivo material stiffness, may serve as biomarkers for the diagnosis and management of aortic aneurysms.
马凡综合征（MFS）是一种结缔组织疾病，由编码原纤维蛋白-1的基因突变引起，原纤维蛋白-1是一种糖蛋白，对大弹性动脉中弹性纤维的组装和稳定性至关重要。MFS与主动脉瘤相关，主动脉瘤通常发生在升主动脉近端，男性的预后更差。动脉瘤发展和预后存在性别和区域特异性差异的机制尚不清楚。我们对4月龄雄性和雌性Fbn1（严重MFS模型）及同窝野生型小鼠的升主动脉、降主动脉、腹主动脉肾上段和腹主动脉肾下段的主动脉几何形状、微观结构重塑和被动生物力学进行了量化，以确定主动脉几何形状、微观结构重塑、生物力学与动脉瘤扩张之间的相关性。我们发现，动脉瘤扩张与无负荷厚度、微观结构重塑（包括弹性纤维丧失、胶原纤维沉积和细胞核数量减少）以及力学指标（包括生理和体外周向材料刚度）密切相关。多变量混合模型显示，无负荷厚度、弹性纤维降解和体外材料刚度可预测动脉瘤扩张，调整后的R = 0.8818。我们的研究结果突出了几何形状、微观结构重塑和生物力学指标作为MFS中个性化主动脉瘤诊断和管理的物理生物标志物的潜力。重要性声明：马凡综合征（MFS）是一种与主动脉瘤相关的遗传性疾病，主动脉瘤具有明显的性别和区域特异性预后。导致这些差异的机制尚不清楚。我们使用严重MFS小鼠模型（Fbn1）来探索雄性和雌性沿主动脉长度的微观结构重塑和被动壁力学差异。我们将这些变化与通过主动脉扩张量化的动脉瘤严重程度相关联。我们发现，主动脉壁无负荷厚度、微观结构重塑和被动力学性能的性别和区域特异性改变在主动脉扩张中起关键作用。我们的研究结果表明，力学指标，特别是体外材料刚度，可作为主动脉瘤诊断和管理的生物标志物。
