Biomedical Engineering Program, University of South Carolina, Columbia, South Carolina.
Physical Therapy Program, Brenau University, Gainesville, Georgia.
Am J Physiol Heart Circ Physiol. 2022 Jan 1;322(1):H44-H56. doi: 10.1152/ajpheart.00255.2021. Epub 2021 Oct 29.
Thoracic aortic aneurysm is one of the manifestations of Marfan syndrome (MFS) that is known to affect men more severely than women. However, the incidence of MFS is similar between men and women. The aim of this study is to show that during pathological aortic dilation, sex-dependent severity of thoracic aortopathy in a mouse model of MFS translates into sex-dependent alterations in cells and matrix of the ascending aorta, consequently affecting aortic biomechanics. Fibrillin-1 C1041G/+ (Het) mice were used as a mouse model of MFS. Ultrasound measurements from 3 to 12 mo showed increased aortic diameter in Het aorta, with larger percentage increase in diameter for males compared with females. Immunohistochemistry showed decreased contractile smooth muscle cells in Het aortic wall compared with healthy aorta, which was accompanied by decreased contractility measured by wire myography. Elastin autofluorescence, second-harmonic generation microscopy of collagen fibers, and passive biomechanical assessments using myography showed more severe damage to elastin fibers, increased medial fibrosis, and increased stiffness of the aortic wall in MFS males but not females. Male and female Het mice showed increased expression of Sca-1-positive adventitial progenitor cells versus controls at young ages. In agreement with clinical data, Het mice demonstrate sex-dependent severity of thoracic aortopathy. It was also shown that aging exacerbates the disease state especially for males. Our findings suggest that female mice are protected from progression of aortic dilation at early ages, leading to a lag in aneurysm growth. Male mice show more severe thoracic aortic changes compared with females, especially at 12 mo of age. Up to 6 mo of age, Sca-1 smooth muscle progenitor cells are more abundant in the adventitia of both male and female Het mice compared with wild types (WTs). Male and female Het mice show similar patterns of expression of Sca-1 cells at early ages.
胸主动脉瘤是马凡综合征（MFS）的表现之一，已知其对男性的影响比女性更严重。然而，MFS 的发病率在男性和女性之间相似。本研究旨在表明，在病理性主动脉扩张过程中，MFS 小鼠模型中主动脉病变的严重程度存在性别依赖性，这种性别依赖性差异会转化为升主动脉细胞和基质的性别依赖性改变，从而影响主动脉生物力学。我们使用纤维连接蛋白 1 C1041G/+（杂合子）（Het）小鼠作为 MFS 的小鼠模型。3 至 12 个月的超声测量显示 Het 主动脉的主动脉直径增大，男性主动脉直径的百分比增加幅度大于女性。免疫组织化学显示 Het 主动脉壁中的收缩性平滑肌细胞减少，与健康主动脉相比，平滑肌细胞的收缩性降低，通过钢丝肌描记术测量得到证实。弹力蛋白自发荧光、胶原纤维二次谐波显微镜和使用肌描记术进行的被动生物力学评估显示，MFS 男性的弹力纤维损伤更严重、中膜纤维化增加、主动脉壁僵硬，但女性没有这种情况。雄性和雌性 Het 小鼠在年轻时与对照组相比，表现出更多的 Sca-1 阳性血管周祖细胞的表达。与临床数据一致，Het 小鼠表现出与性别相关的严重程度的胸主动脉病变。研究还表明，衰老会使疾病状态恶化，特别是对男性而言。我们的研究结果表明，雌性小鼠在早期受到保护，防止主动脉扩张的进展，从而导致动脉瘤生长滞后。与雌性小鼠相比，雄性小鼠的胸主动脉变化更为严重，尤其是在 12 月龄时。在 6 月龄之前，雄性和雌性 Het 小鼠的血管周 Sca-1 平滑肌祖细胞比野生型（WT）小鼠更为丰富。在早期，雄性和雌性 Het 小鼠的 Sca-1 细胞表达模式相似。
