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_Ca2.3) 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_Ca2.3 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_Ca2.3 blockers in both young and aged rats. However, exercise restored both the age-related and the TRPV4-mediated and K_Ca2.3-mediated EDHF responses.
Conclusion: These results suggest an important role for the TRPV4-K_Ca2.3 signaling undergirding the beneficial effect of exercise to ameliorate age-related arterial dysfunction.
Keywords: endothelium, EDHF, exercise, TRPV4, K_Ca2.3, aging