title: Aging impairs smooth muscle-mediated regulation of aortic stiffness: a defect in shock absorption function?
abstract: Increased aortic stiffness is an early and independent biomarker of cardiovascular disease. Here we tested the hypothesis that vascular smooth muscle cells (VSMCs) contribute significantly to aortic stiffness and investigated the mechanisms involved. The relative contributions of VSMCs, focal adhesions (FAs), and matrix to stiffness in mouse aorta preparations at optimal length and with confirmed VSMC viability were separated by the use of small-molecule inhibitors and activators. Using biomechanical methods designed for minimal perturbation of cellular function, we directly quantified changes with aging in aortic material stiffness. An alpha adrenoceptor agonist, in the presence of N(G)-nitro-l-arginine methyl ester (l-NAME) to remove interference of endothelial nitric oxide, increases stiffness by 90-200% from baseline in both young and old mice. Interestingly, 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. 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) VSMCs are a surprisingly large component of aortic stiffness at physiological lengths and 2) regulation of the VSMC component through FA signaling and hence plasticity is impaired with aging, diminishing the aorta's normal shock absorption function in response to stressors.
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Boston University, Boston, Massachusetts; and Department of Health Sciences, Sargent College, Boston University, Boston, Massachusetts.
authors.forename: Yuan Z
authors.initials: YZ
authors.lastname: Gao
authors.affiliation: Department of Health Sciences, Sargent College, Boston University, Boston, Massachusetts.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Saphirstein
authors.affiliation: Department of Health Sciences, Sargent College, Boston University, Boston, Massachusetts.
authors.forename: Rina
authors.initials: R
authors.lastname: Yamin
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Boston University, Boston, Massachusetts; and.
authors.forename: Bela
authors.initials: B
authors.lastname: Suki
authors.affiliation: Department of Health Sciences, Sargent College, Boston University, Boston, Massachusetts kmorgan@bu.edu.
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Morgan
mesh_terms: D000322:Adrenergic Agonists / Q000494:pharmacology; D000375:Aging; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022001:Focal Adhesions / Q000378:metabolism*; D006439:Hemodynamics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013314:Stress, Mechanical; D059289:Vascular Stiffness; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C412373:AG 1879; D000322:Adrenergic Agonists; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D010656:Phenylephrine; D019061:src-Family Kinases; D019331:NG-Nitroarginine Methyl Ester
keywords: Src; alpha agonist; focal adhesion; phosphotyrosine; smooth muscle