TcMAC21 mouse model recapitulates abnormal vascular physiology observed in humans with Down syndrome

Abstract

People with Down syndrome (DS) have abnormal vascular physiology, demonstrated by low systolic blood pressure (BP) and low aortic stiffness that are accompanied by endothelial dysfunction. The TcMAC21 mouse model of DS has many features observed in people with DS, although vascular physiology has not been studied. At 4 months old, male and female TcMAC21 mice exhibited lower systolic BP and aortic stiffness, as determined by aortic pulse wave velocity, which are accompanied by blunted carotid artery flow-mediated vasodilation, indicating endothelial dysfunction, compared to euploid (i.e., control) mice. To determine a potential mechanism for blunted flow-mediated vasodilation, we assessed endothelial glycocalyx properties, which mechanotransduces fluid shear stress to the endothelial cells, stimulating flow-mediated vasodilation. We observed a lower glycocalyx thickness in the mesenteric microcirculation of TcMAC21 mice. Vascular abnormalities in TcMAC21 mice were accompanied by systemic inflammation. 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 support the use of the TcMAC21 mouse model to study the vascular physiology in people with DS and may provide translational insight into the role of glycocalyx in vascular abnormalities in DS.

Keywords: aortic stiffness; blood pressure; endothelium; glycocalyx; trisomy 21.

FIGURE 1

Breeding scheme of TcMAC21 and euploid mice (a) and identification of GFP‐positive, TcMAC21 and GFP‐negative, euploid mice (b).

FIGURE 2

Group comparisons in euploid and TcMAC21 mice were analyzed using unpaired t‐test to identify differences in systolic blood pressure (BP; a; n = 15–18 mice/group) and aortic pulse wave velocity (PWV; b; n = 19–20 mice/group). *p < 0.05 versus euploid. Data are individual values (males = circles, females = triangles) and means±SEM.

FIGURE 3

Group comparisons in euploid and TcMAC21 mice were analyzed using unpaired t‐test to identify differences in aortic lumen diameter (a; n = 16–18 mice/group), aortic medial cross‐sectional area (b; n = 18–19 mice/group), elastin content (c; n = 14–16 mice/group), and collagen content (d; n = 16–17 mice/group). Images are accompanied by representative images of collagen and elastin staining. Black scale bars are equal to 200 μm. *p < 0.05 versus euploid. Data are individual values (males = circles, females = triangles) and means ± SEM.

FIGURE 4

Group × Gradient/Concentration comparisons in euploid and TcMAC21 mice were analyzed using two‐way, mixed model ANOVA with Holm‐Šídák post hoc test to identify differences in carotid artery vasoconstriction to phenylephrine (a; n = 19–21 mice/group), as well as vasodilation to changes in pressure gradient in the absence (solid line) and presence of L‐NAME (dashed line) (b; n = 9–14 mice/group), acetylcholine in absence (solid line) and presence of L‐NAME (dashed line) (c; n = 17–20 mice/group), and sodium nitroprusside (d; n = 15 mice/group). *p < 0.05 versus euploid. †p < 0.05 versus L‐NAME within the group. Data are means ± SEM.

FIGURE 5

Group comparisons in euploid and TcMAC21 mice were analyzed using unpaired t‐test or Mann–Whitney U test to identify differences in microvascular density (a; n = 19–22 mice/group), flow (b; n = 18–22 mice/group), red blood cell (RBC) velocity (c; n = 19–22 mice/group), capillary blood volume (CBV; d; n = 19–22 mice/group), perfused boundary region (PBR; e; n = 19–22 mice/group), and glycocalyx thickness (f; n = 19–22 mice/group), . Data are individual values (males = circles, females = triangles) and means ± SEM.

FIGURE 6

Group × Time comparisons in euploid and TcMAC21 mice were analyzed using two‐way, mixed model ANOVA with Holm‐Šídák post hoc test to identify differences in blood glucose in response to glucose tolerance test (GTT: a; n = 19–20 mice/group). An unpaired t‐test was used to identify differences in GTT area under the curve (AUC) between groups (b; n = 19–20 mice/group). A two‐way, mixed model ANOVA with Holm‐Šídák post hoc test was used to identify differences in blood glucose in response to insulin tolerance test (ITT; c; n = 19–20 mice/group; n = 19–20 mice/group). An unpaired t‐test was used to identify differences in ITT AUC between groups (d). *p < 0.05 versus euploid. Data are individual values (males = circles, females = triangles) and means ± SEM.

FIGURE 7

Group comparisons in euploid and TcMAC21 mice were analyzed using unpaired t‐test or Mann–Whitney U test to identify differences in blood concentrations of white blood cells (WBC; a; n = 19–22 mice/group), monocytes (b; n = 18–22 mice/group), lymphocytes (c; n = 19–22 mice/group), neutrophils (d; n = 19–22 mice/group), eosinophils (e; n = 19–22 mice/group), basophils (f; n = 18–21 mice/group), red blood cells (RBC; g; n = 19–22 mice/group), mean corpuscular volume (MCV; h; n = 19–22 mice/group), mean corpuscular hemoglobin (MCH; i; n = 19–22 mice/group), and platelet (j; n = 19–22 mice/group). Data are individual values (males = circles, females = triangles) and means ± SEM.

FIGURE 8

Group comparisons in euploid and TcMAC21 mice were analyzed using unpaired t‐test or Mann–Whitney U test to identify differences in plasma concentrations of G‐CSF (a; n = 12 mice/group), IL‐1β (b; n = 12 mice/group), LIF (c; n = 12 mice/group), GM‐CSF (d; n = 12 mice/group), IFNγ (e; n = 12 mice/group), IL‐2 (f; n = 12 mice/group), IL‐6 (g; n = 11–12 mice/group), IL‐10 (h; n = 12 mice/group), IL‐17 (i; n = 12 mice/group), MIP‐1α (j; n = 12 mice/group), VEGF (k; n = 12 mice/group), and TNF‐ α (l; n = 12 mice/group). Data are individual values (males = circles, females = triangles) and means ± SEM.