Nrf2 deficiency blunts exercise training-induced adaptations of coronary resistance arteries

Exercise training upregulates nuclear factor erythroid 2-related factor 2 (Nrf2) expression and antioxidant production in various tissues; however, little is known about the role of Nrf2 in exercise training-induced adaptations of blood vessels. This study investigated how deletion of Nrf2 affects vasomotor function in coronary resistance arteries in sedentary and exercise-trained rats. Wild-type (WT) and Nrf2 knockout (KO) rats underwent 10 weeks of treadmill exercise or remained sedentary. Coronary resistance arteries were isolated for assessment of vasomotor responses. In resistance arteries from Nrf2 KO rats, endothelin-induced constriction was blunted, but exercise training partially restored responsiveness to endothelin; after exercise training, responses to endothelin were not different between arteries from WT and Nrf2 KO rats. Similarly, KCl-induced constriction was reduced in arteries from Nrf2 KO rats, but exercise training reversed this loss of responsiveness to KCl. Nitric oxide (NO)-mediated vasodilation of coronary resistance arteries was not altered by deletion of Nrf2; however, exercise training enhanced NO-mediated dilation in arteries from WT, but not Nrf2 KO rats. Similarly, exercise training increased vasodilation to low concentrations of potassium (10 and 20 mM KCl) in arteries from WT, but not Nrf2 KO rats. These findings suggest that Nrf2 is critical to maintenance of contractile responses in coronary resistance arteries, but exercise training can restore contractile function through Nrf2-independent mechanisms. In contrast, vasodilatory responses to NO and low-level potassium are maintained in coronary resistance arteries from Nrf2-deficient rats, but exercise training fails to enhance these vasodilatory responses in the absence of Nrf2.