Primary Prevention of Age‐ and Western Diet‐Associated Vascular Endothelial Dysfunction by Voluntary Aerobic Exercise in Mice: Role of Mitochondrial Oxidative Stress
Authors: Clayton Zachary S , Gioscia‐Ryan Rachel A , Rossman Matthew J , Richey James J , Cuevas Lauren M , Battson Micah L , Zigler Melanie C , Seals Douglas R 
Published: June 2021

Age‐related arterial endothelial dysfunction is a key antecedent of cardiovascular disease, largely caused by reductions in nitric oxide (NO) bioavailability as a result of superoxide‐associated oxidative stress. A western‐style diet (WD; high fat/high sucrose/low fiber) accelerates age‐related declines in endothelial function. Aerobic exercise reverses endothelial dysfunction in old mice, even in the presence of a WD. However, it is unknown whether consumption of a WD over the lifespan accelerates vascular endothelial dysfunction, and whether regular voluntary aerobic exercise can prevent the progressive impairments in endothelial function that occur over the lifespan (primary prevention) when consuming either a non‐Western (healthy) diet or WD. To investigate these questions, we studied 4 cohorts of mice (consuming normal chow (NC) or WD, without or with access to voluntary wheel running (VWR) beginning at 3 months (mo) of age) and assessed endothelial function (ex vivo carotid artery endothelial dependent dilation [EDD]) and associated underlying mechanisms at 6, 13, 19 and 27 mo. Maximal acetylcholine (ACh)‐stimulated EDD was reduced by 30% (P < 0.001) in 27 mo old mice fed NC; in contrast, WD consumption impaired maximal EDD at 6 mo and throughout the lifespan. VWR preserved EDD in both NC and WD fed mice at all ages. Group differences in EDD were driven by differences in NO bioavailability, as EDD was not different among the groups after administration of the NO‐synthase inhibitor, L‐NAME. Smooth muscle sensitivity to NO (i.e., dilation in response to the NO donor sodium nitroprusside) was unaltered with age, diet or exercise. Age‐ and diet‐related decreases in EDD were mediated, in part, by increased mitochondrial reactive oxygen species (MtROS)‐related suppression of EDD, as indicated by complete restoration of maximal EDD in 27 mo old mice fed a NC diet and WD fed mice at 19 mo (WD fed mice did not survive to 27 mo) by ex vivo incubation with the mitochondria‐targeted antioxidant MitoQ. VWR prevented MtROS‐related suppression of EDD with age and WD. Oxidative stress (aortic superoxide production by electron paramagnetic resonance spectroscopy) was increased throughout the lifespan in NC (2‐fold; P < 0.05) and WD (2.3‐fold; P < 0.0001) mice. MtROS contributed to group differences in oxidative stress, as Mt‐specific aortic superoxide production was increased in WD and attenuated by VWR. Overall, these findings demonstrate that consuming a WD accelerates age‐related declines in endothelial function, associated with decreased NO bioavailability and increased MtROS‐related oxidative stress. Regular voluntary aerobic exercise preserves vascular endothelial function throughout the lifespan in mice and protects against the adverse influence of a WD.Support or Funding InformationNIH R01 HL107120 NIH T32 DK007135This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.