Vascular oxidative stress promotes aortic stiffening (867.2)

Abstract

Oxidative stress correlates with arterial stiffness in clinical studies. Reactive oxygen species (ROS) contribute to blood pressure elevation, vascular smooth muscle hypertrophy and vascular dysfunction in hypertension. We hypothesized that vascular ROS induce aortic stiffening, which in turn promotes systolic hypertension with aging. We created mice overexpressing p22phox in smooth muscle (tgsm/p22phox mice), which have a constitutive increase in vascular ROS production. Six month old tgsm/p22phox mice were normotensive at baseline (118±6 systolic, mmHg), but had increased aortic stiffness as indicated by the leftward shift on stress‐strain curves. Aortic collagen level, as detected by hydroxyproline content, was increased in tgsm/p22phox mice compared to age‐matched C57Bl/6 mice (76.3±11.9 vs. 43.2±7.2 ng/μg total protein). At 9 months of age, aortic stiffening did not further increase but these mice developed mild hypertension (137±11 systolic), demonstrating that excessive ROS first promotes aortic stiffening and subsequently hypertension. Tempol, a superoxide dismutase mimetic, normalized blood pressure (117±10 systolic), reduced vascular collagen deposition (37.5±9.5 ng/μg) and prevented aortic stiffening in these mice, suggesting a role of vascular ROS in aging‐induced aortic stiffening. ROS oxidize arachidonic acid to produce isoketals, known to cross‐link lysines and promote protein cross‐linking, which could lead to vascular stiffening. Immunohistochemistry indicated a marked increase of isoketals in the aorta and peri‐aortic fat of tgsm/p22phox mice, which was prevented by 2‐hydroxybenzylamine (2‐HOBA), a scavenger of isoketals. 2‐HOBA also reduced blood pressure, prevented collagen deposition and aortic stiffening in tgsm/p22phox mice treated from 3 months to 9 months of age. We conclude that ROS promote aortic stiffening and that this might in part be due to isoketal formation and protein crosslinking.Grant Funding Source: Supported by NIH R01 grant HL105294