Kamau Anne N, Sakamuri Anil, Okoye Delphine O, Sengottaian Divya, Cannon Jennifer, Guerrero-Millan Josefa, Sullivan Jennifer C, Miller Kristin S, Liu Yutao, Ogola Benard O
Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, United States.
Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, United States.
Am J Physiol Heart Circ Physiol. 2025 Mar 1;328(3):H472-H483. doi: 10.1152/ajpheart.00432.2024. Epub 2025 Jan 28.
The contribution of sex hormones to cardiovascular disease, including arterial stiffness, is established; however, the role of sex chromosome interaction with sex hormones, particularly in women, is lagging. Arterial stiffness depends on the intrinsic properties and transmural wall geometry that comprise a network of cells and extracellular matrix (ECM) proteins expressed in a sex-dependent manner. In this study, we used four-core genotype (FCG) mice to determine the relative contribution of sex hormones versus sex chromosomes or their interaction with arterial stiffness. Gonadal intact FCG mice included females (F) and males (M) with either XX or XY sex chromosomes ( = 9-11/group). We isolated the thoracic aorta, and a tissue puller was used to assess structural resistance to changes in shape under control, collagenase, or elastase conditions. We determined histological collagen area fraction and evaluated aortic ECM genes by PCR microarrays followed by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Stress-strain curves showed higher elastic modulus ( < 0.001), denoting decreased distensibility in XXF compared with XYF aortas, which were significantly reversed by collagenase and elastase treatments ( < 0.01). Aortic gene expression analysis indicated a significant reduction in , , and in the XXF versus XYF aorta ( < 0.05). Uniaxial stretching of XXF aortic vascular smooth muscle cells indicated decreased , , and genes. We observed a significant ( < 0.05) reduction in Masson's trichrome staining in collagenase but not elastase-treated aortic rings compared with the control. The increased aortic elastic modulus in XXF compared with XYF mice suggests a decrease in aortic distensibility mediated by a reduction in ECM genes. FCG mice model can segregate vascular phenotypes by sex hormones, sex chromosomes, and their interaction. We show increased aortic stiffening in XX versus XY female mice and decreased ECM genes, suggesting decreased distensibility and impaired mechanotransduction in XXF versus XYF mice aortas. Therefore, the XX versus XY differences imply a unique role for sex chromosomes in regulating aortic integrity and ECM genes in female mice.
性激素对心血管疾病（包括动脉僵硬度）的影响已得到证实；然而，性染色体与性激素相互作用的作用，尤其是在女性中，仍研究不足。动脉僵硬度取决于内在特性和跨壁壁几何形状，它们由以性别依赖方式表达的细胞和细胞外基质（ECM）蛋白网络组成。在本研究中，我们使用四核心基因型（FCG）小鼠来确定性激素与性染色体的相对贡献或它们与动脉僵硬度的相互作用。性腺完整的FCG小鼠包括具有XX或XY性染色体的雌性（F）和雄性（M）（每组n = 9 - 11）。我们分离出胸主动脉，并使用组织拉拔器在对照、胶原酶或弹性蛋白酶条件下评估对形状变化的结构阻力。我们确定了组织学胶原面积分数，并通过PCR微阵列随后进行定量逆转录聚合酶链反应（RT-qPCR）评估主动脉ECM基因。应力-应变曲线显示弹性模量更高（P < 0.001），表明与XYF主动脉相比，XXF主动脉的扩张性降低，胶原酶和弹性蛋白酶处理可显著逆转这种情况（P < 0.01）。主动脉基因表达分析表明，与XYF主动脉相比，XXF主动脉中COL1A1、COL3A1和ELN显著减少（P < 0.05）。XXF主动脉血管平滑肌细胞的单轴拉伸表明COL1A1、COL3A1和ELN基因减少。与对照相比，我们观察到胶原酶处理而非弹性蛋白酶处理的主动脉环中Masson三色染色显著减少（P < 0.05）。与XYF小鼠相比，XXF小鼠主动脉弹性模量增加表明ECM基因减少介导了主动脉扩张性降低。FCG小鼠模型可以通过性激素、性染色体及其相互作用来区分血管表型。我们显示XX雌性小鼠与XY雌性小鼠相比主动脉僵硬度增加，ECM基因减少，表明XXF与XYF小鼠主动脉的扩张性降低和机械转导受损。因此，XX与XY的差异意味着性染色体在调节雌性小鼠主动脉完整性和ECM基因方面具有独特作用。
