Mechanisms of the Shock Absorber Function in Proximal Aorta

Abstract

Increased aortic stiffness is an early and independent biomarker of cardiovascular disease. Here we used biomechanical methods designed for minimal perturbation of cellular function to determine material stiffness in proximal mouse aorta and investigate mechanisms of its changes with aging. In mouse aorta preparations at optimal length and with confirmed vascular smooth muscle (VSM) viability, the relative contributions of VSM, focal adhesions (FAs), and extracellular matrix to aortic stiffness were observed to be quantifiably separable by changes in temperature, as well as the use of small molecule inhibitors and activators. In the presence of an alpha adrenoceptor agonist, and L-NAME to remove interference of endothelial nitric oxide, the VSM contributes up to half of total aortic stiffness. Interestingly, agonist-induced stiffness increases are robustly suppressed by the Src kinase inhibitor PP2 in young but not old mice. Phosphotyrosine screening revealed, with aging, a biochemical signature of markedly impaired agonist-induced FA remodeling previously associated with Src signaling. Furthermore, protein expression measurement confirmed a decrease in Src expression with aging. Thus, we report here an additive model for the in vitro biomechanical components of the mouse aortic wall in which: 1) VSM activity accounts for a surprisingly large component of aortic stiffness under physiologic conditions and 2) regulation of this VSM component through FA signaling and hence plasticity is impaired with aging, diminishing the aorta's normal shock absorber function in response to stressors (Figure 1). Support: Evans Center Aortic Stiffness Arc, P01HL86655.