<p>Exercise restores impaired endothelium-derived hyperpolarizing factor–mediated vasodilation in aged rat aortic arteries via the TRPV4-K_Ca2.3 signaling complex</p>

Abstract

Background Aging leads to structural and functional changes in the vasculature characterized by arterial endothelial dysfunction and stiffening of large elastic arteries and is a predominant risk factor for cardiovascular disease, the leading cause of morbidity and mortality in modern societies. Although exercise reduces the risk of many age-related diseases, including cardiovascular disease, the mechanisms underlying the beneficial effects of exercise on age-related endothelial function fully elucidated. Purpose The present study explored the effects of exercise on the impaired endothelium-derived hyperpolarizing factor (EDHF)–mediated vasodilation in aged arteries and on the involvement of the transient receptor potential vanilloid 4 (TRPV4) channel and the small-conductance calcium-activated potassium (K Ca 2.3) channel signaling in this process. Methods Male Sprague-Dawley rats aged 19–21 months were randomly assigned to a sedentary group or to an exercise group. Two-month-old rats were used as young controls. Results We found that TRPV4 and K Ca 2.3 isolated from primary cultured rat aortic endothelial cells pulled each other down in co-immunoprecipitation assays, indicating that the two channels could physically interact. Using ex vivo functional arterial tension assays, we found that EDHF-mediated relaxation induced by acetylcholine or by the TRPV4 activator GSK1016790A was markedly decreased in aged rats compared with that in young rats and was significantly inhibited by TRPV4 or K Ca 2.3 blockers in both young and aged rats. However, exercise restored both the age-related and the TRPV4-mediated and K Ca 2.3-mediated EDHF responses. Conclusion These results suggest an important role for the TRPV4-K Ca 2.3 signaling undergirding the beneficial effect of exercise to ameliorate age-related arterial dysfunction.

The Transient Receptor Potential Vanilloid 4 Channel and Cardiovascular Disease Risk Factors

“…Because increasing the TRPV4 expression using gene delivery by lentiviral vectors restored the reduced TRPV4 agonist-and flow-induced vasorelaxations in aged rats, reduced expression of endothelial TRPV4 appears causally related to the age-associated endothelial dysfunction in this model (Du et al, 2016). Reduced TRPV4 agonist-induced vasorelaxation, possibly due to impaired TRPV4-SK Ca signaling, was reported in the thoracic aortas of aged (19-to 21-month-old) Sprague Dawley rats compared with that in young (2-month-old) rats (Huang et al, 2019). Interestingly, 3 months of consistent exercise reversed the age-related impairment of the TRPV4mediated vasorelaxation, although the mechanisms underlying the restoration of function remain unknown (Huang et al, 2019).…”

“…Reduced TRPV4 agonist-induced vasorelaxation, possibly due to impaired TRPV4-SK Ca signaling, was reported in the thoracic aortas of aged (19-to 21-month-old) Sprague Dawley rats compared with that in young (2-month-old) rats (Huang et al, 2019). Interestingly, 3 months of consistent exercise reversed the age-related impairment of the TRPV4mediated vasorelaxation, although the mechanisms underlying the restoration of function remain unknown (Huang et al, 2019).…”

Intrinsic and Extrinsic Contributors to the Cardiac Benefits of Exercise

“… 113 Consistent with a possible role for TRPV4, exercise training reversed age-related decline in TRPV4-dependent, endothelium-derived hyperpolarizing factor–mediated dilation in rat aortic arteries. 114 Molecular mechanisms underlying exercise benefits may also differ in the context of age or disease, for example, exercise training reduced vessel wall collagen-to-elastin ratio in coronary arterioles of old but not young rats. 93 , 94 These observations suggest exercise-inspired therapeutics targeting the microvasculature could benefit cardiovascular diseases and cardiac aging.…”

Effects of Different Kinds of Physical Activity on Vascular Function

“…Moreover, in a multivariate regression analysis, physical activity was discovered to be a significant predictor of both the pressure–strain elastic modulus ( p = 0.001) and pulse wave velocity ( p < 0.001), even if both the associations were attenuated after the inclusion of heart rate in the model ( p = 0.042 and 0.007, respectively). Again, this paper highlighted the important role of physical activity for heart rate as a mediator of the effects on vascular function [ 13 ], combined with receding microvascular remodeling, normalization of the capillary density, ameliorating the function of the vascular tree and, finally, counteracting the oxidative stress phenomenon [ 19 , 20 , 21 , 22 ]. All the evidence mentioned above refers to the efficacy of aerobic training, but what evidence do we have for different kinds of exercise?…”