Search

Mice are the most common animal model to investigate human disease and explore physiology. Mice are practical, cost efficient, and easily used for genetic manipulations. Although variability in cardiac structure and function among mouse strains is well noted, the effect of mouse strain on vascular stiffness indices is not known. Here, we compared mouse strain-dependent differences in key vascular stiffness indices among frequently used inbred mouse strains-C57Bl/6J, 129S, and Bl6/129S. In young healthy animals, baseline blood pressure and heart rate were identical in all strains, and independent of gender. However, both active in vivo and passive ex vivo vascular stiffness indices exhibited distinct differences. Specifically, both male and female 129S animals demonstrated the highest tensile stiffness, were least responsive to acetylcholine-induced vasorelaxation, and showed the lowest pulse wave velocity (PWV), an index of in vivo stiffness. C57Bl/6J mice demonstrated the highest PWV, lowest tensile stiffness, and the highest response to acetylcholine-induced vasorelaxation. Interestingly, within each strain, female mice had more compliant aortas. C57Bl/6J mice had thinner vessel walls with fewer layers, whereas 129S mice had the thickest walls with the most layers. Values in the Bl6/129S mixed background mice fell between C57Bl/6J and 129S mice. In conclusion, we show that underlying vascular properties of different inbred wild-type mouse strains are distinct, despite superficial similarities in blood pressure. For each genetic modification, care should be taken to identify proper controls, and conclusions might need to be verified in more than one strain to minimize the risk of false positive studies.

Background: Vascular aging is closely associated with increased vascular stiffness. It has recently been demonstrated that decreased nitric oxide (NO)-induced S-nitrosylation of tissue transglutaminase (TG2) contributes to age-related vascular stiffness. In the current study, we tested the hypothesis that exercise restores NO signaling and attenuates vascular stiffness by decreasing TG2 activity and cross-linking in an aging rat model., Methods and Results: Rats were subjected to 12 weeks of moderate aerobic exercise. Aging was associated with diminished phosphorylated endothelial nitric oxide synthase and phosphorylated vasodilator-stimulated phosphoprotein abundance, suggesting reduced NO signaling. TG2 cross-linking activity was significantly increased in old animals, whereas TG2 abundance remained unchanged. These alterations were attenuated in the exercise cohort. Simultaneous measurement of blood pressure and pulse wave velocity (PWV) demonstrated increased aortic stiffness in old rats, compared to young, at all values of mean arterial pressure (MAP). The PWV-MAP correlation in the old sedentary and old exercise cohorts was similar. Tensile testing of the vessels showed increased stiffness of the aorta in the old phenotype with a modest restoration of mechanical properties toward the young phenotype with exercise., Conclusions: Increased vascular stiffness during aging is associated with decreased TG2 S-nitrosylation, increased TG2 cross-linking activity, and increased vascular stiffness likely the result of decreased NO bioavailability. In this study, a brief period of moderate aerobic exercise enhanced NO signaling, attenuated TG cross-linking activity, and reduced ex vivo tensile properties, but failed to reverse functional vascular stiffness in vivo, as measured by PWV.

Nitric oxide (NO) can modulate arterial stiffness by regulating both functional and structural changes in the arterial wall. Tissue transglutaminase (TG2) has been shown to contribute to increased central aortic stiffness by catalyzing the cross-linking of matrix proteins. NO S-nitrosylates and constrains TG2 to the cytosolic compartment and thereby holds its cross-linking function latent. In the present study, the role of endothelial NO synthase (eNOS)-derived NO in regulating TG2 function was studied using eNOS knockout mice. Matrix-associated TG2 and TG2 cross-linking function were higher, whereas TG2 S-nitrosylation was lower in the eNOS(-/-) compared with wild-type (WT) mice. Pulse-wave velocity (PWV) and blood pressure measured noninvasively were elevated in the eNOS(-/-) compared with WT mice. Intact aortas and decellularized aortic tissue scaffolds of eNOS(-/-) mice were significantly stiffer, as determined by tensile testing. The carotid arteries of the eNOS(-/-) mice were also stiffer, as determined by pressure-dimension analysis. Invasive methods to determine the PWV-mean arterial pressure relationship showed that PWV in eNOS(-/-) and WT diverge at higher mean arterial pressure. Thus eNOS-derived NO regulates TG2 localization and function and contributes to vascular stiffness.