Sexual dimorphism in the downregulation of extracellular matrix genes contributes to aortic stiffness in female mice

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 (n = 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 (P < 0.001), denoting decreased distensibility in XXF compared with XYF aortas, which were significantly reversed by collagenase and elastase treatments (P < 0.01). Aortic gene expression analysis indicated a significant reduction in Emilin1, Thbs2, and Icam1 in the XXF versus XYF aorta (P < 0.05). Uniaxial stretching of XXF aortic vascular smooth muscle cells indicated decreased Thbs2, Ctnna1, and Ecm1 genes. We observed a significant (P < 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.NEW & NOTEWORTHY 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.