Female C57Bl/6N mice are a viable model of human aortic aging: Aortic stiffness and structure and systemic inflammation
Authors: Longtine Abigail , Venkatasubramanian Ravinandan , Zigler Melanie , Lindquist Alexandra , Mahoney Sophia , Greenberg Nathan , VanDongen Nicholas , Ludwig Katelyn , Moreau Kerrie , Seals Douglas , Clayton Zachary 
Published: May 2023

The aorta stiffens with aging in both men and women and predicts cardiovascular mortality. Stiffening occurs largely due to aortic wall structural remodeling induced, in part, by chronic low-grade inflammation. Use of animal models in biomedical research is essential for screening interventions for safety/efficacy and providing mechanistic insight that is difficult, or impossible, to obtain in humans. Male C57Bl/6N mice are an established model of aortic aging and have predominantly been used to determine mechanisms of and investigate interventions for mitigating age-related vascular changes. Although some studies have investigated mechanisms of artery stiffening in female mice in midlife, there is still a paucity of information regarding whether female mice are an appropriate model of age-related aortic stiffening/structural remodeling, especially in late life. Purpose: To determine if female C57Bl/6N mice are an appropriate model (i.e., reflective of the human condition) of age-related aortic stiffening, associated structural remodeling and systemic inflammation. Methods and Results: Data are mean ± SE. Aortic stiffness (pulse wave velocity) was higher in old (O; 27-29 mo) vs. young adult (Y; 6-7 mo) male (M) and female (F) C67Bl/6N mice (cm/sec: YM: 347±27, YF: 345±23, OM: 401±32, OF: 413±45; p<0.01; n=10-15/group). Aortic elasticity (pin myography; elastic modulus obtained from a stress-strain curve) was lower in older animals (kPa: YM: 500±52, YF: 529±109, OM: 324±71, OF: 367±32; p<0.01; n=6-9/group), occurred in conjunction with and was related to higher plasma levels of the elastin-degrading enzyme matrix-metalloproteinase-9 (ng/mL: YM: 20±1, YF: 18±4, OM: 49±6, OF: 38±4; p<0.01; r2=0.29, p<0.01; n=9/group), and was accompanied by higher numbers of aortic elastin breaks (YM: 3.4±0.4, YF: 3.5±0.5, OM: 5.6±0.8, OF: 6.2±0.6; p<0.01; n=4-5/group) and higher abundance of adventitial collagen-1 (immunofluorescence in 7 μM segments of thoracic aorta; arbitrary units (A.U.) of intensity: YM: 87±7, YF: 74±5, OM: 123±1, OF: 107±1; p<0.01; n=5/group). Plasma levels of the inflammatory cytokines (cytokine antibody array; A.U. of intensity; n=10-14/group) interferon-γ (YM: 10±2, YF: 16±3, OM: 21±4, OF: 24±6; p=0.04), interleukin (IL)-6 (YM: 30±2, YF: 28±2, OM: 63±8, OF: 83±11; p<0.01) and monocyte chemoattractant protein (MCP)-1 (YM: 7±1, YF: 9±4, OM: 11±2, OF: 14±2; p=0.01) were higher in older animals. There were no sex differences in any of these outcomes (all p>0.15). Aortic elasticity was inversely related to IL-6 (r2=0.49, p<0.01) and MCP-1 (r2=0.12, p=0.06), whereas aortic stiffness was positively related to IL-6 (r2=0.12, p=0.02) (cytokines log transformed to account for skewness). Conclusions: Female mice exhibit aortic stiffening and structural remodeling, and associated increases in MMP-9 and systemic inflammation with aging, similar to male mice, and thus are an appropriate model of human aortic aging for use in biomedical investigations. NIH T32 AG000279, F31 FHL160173A, K99 HL159241 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.