TcMAC21 Mouse Model of Down Syndrome Exhibits Abnormal Vascular Physiology Observed in People with Down Syndrome

Down syndrome (DS), caused by the triplication of human chromosome 21 (HSA21), is the most common genetic disorder in the United States. The population size and life expectancy of people with DS have been expanding over the last several decades due to the treatment of congenital heart disease, which affects ~50% of the DS population. Still, cardiovascular disease (CVD) remains the leading cause of death in people with DS. People with DS are also at a higher risk for CVD complications such as coronary and cerebral artery diseases compared to the general population. A central feature of CVD is vascular dysfunction (i.e., elevated systolic blood pressure [BP], aortic stiffening, and endothelial dysfunction), which precedes and contributes to CVD. People with DS have abnormal vascular physiology, demonstrated by low systolic BP and low aortic stiffness that are accompanied by endothelial dysfunction. Currently, the most popular preclinical model of DS is the Ts65dn mouse, which contains ~52% of HSA21 protein-coding genes and, historically, has not translated well to humans. Recently, the TcMAC21 mouse model of DS was developed, which contains ~93% of HSA21 protein-coding genes. TcMAC21 mice demonstrate many features observed in people with DS, although vascular physiology has yet to be investigated. Thus, we sought to examine vascular physiology in male and female TcMAC21 and euploid (i.e., control) mice (n=19-22/group). At 4 mo old, male and female TcMAC21 mice exhibited lower systolic BP (TcMAC21: 102±1 vs. Euploid: 108±1 mmHg, p<0.05) and aortic stiffness, as determined by aortic pulse wave velocity (TcMAC21: 272±5 vs. Euploid: 291±3 cm/sec, p<0.05). In aortic cross-sections, elastin content was higher in TcMAC21 mice (TcMAC21: 1.14±0.03 vs. Euploid: 1.00±0.05 AU, p<0.05), while aortic collagen content was similar between groups (TcMAC21: 1.04±0.04 vs. Euploid: 1.00±0.04 AU, p>0.05). TcMAC21 mice also had endothelial dysfunction, indicated by blunted max flow-mediated vasodilation (FMV) (TcMAC21: 21.0±5.0 vs. Euploid: 5.2±3.2%, p<0.05). Max vasodilation in response to acetylcholine (TcMAC21: 82.7±12.8 vs. Euploid: 86.5±1.1 %, p>0.05) and sodium nitroprusside (TcMAC21: 91.8±0.7 vs. Euploid: 91.6±0.7 %, p>0.05) were similar between groups, which implies that blunted FMV is not due to impaired endothelial cell signaling or smooth muscle vasodilatory capacity. To determine a potential mechanism for blunted FMV, we assessed glycocalyx properties. The glycocalyx is a gel-like structure on the luminal surface of endothelium that is critical to vascular health, as it mechanotransduces fluid shear stress from flow to the endothelial cells, which stimulates FMV. We observed a lower glycocalyx thickness in TcMAC21 mice (TcMAC21: 0.30±0.05 vs. Euploid: 0.54±0.04 µm, p<0.05). Vascular abnormalities in TcMAC21 mice were also accompanied by systemic inflammation, as indicated by higher levels of circulating monocytes (TcMAC21: 0.9±0.3 vs. Euploid: 0.3±0.1 10 3 /µL, p<0.05) and plasma pro-inflammatory cytokines G-CSF (TcMAC21: 1.7±0.1 vs. Euploid: 1.0±0.1 AU, p<0.05) and IL-1β (TcMAC21: 1.2±0.1 vs. Euploid: 1.0±0.0 AU, p<0.05) and a lower level of anti-inflammatory cytokine LIF (TcMAC21: 0.8±0.0 vs. Euploid: 1.0±0.1 AU, p<0.05) in TcMAC21 mice. This is the first study to examine vascular physiology in the TcMAC21 mouse model of DS and investigate glycocalyx properties in any model of DS, including humans. Taken together, these findings provide evidence for the use of TcMAC21 mouse model to study the abnormal vascular physiology in people with DS and may provide translational insight into the role of glycocalyx in vascular abnormalities in DS. This study was funded in part by a grant from the National Institutes of Health (R00 AT010017). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.