Increased cGMP improves microvascular exercise training adaptations in diet-induced obesity

With the development of atherosclerosis, impaired microvascular function can result in diminished capacity for ambulation and is a risk factor for type 2 diabetes. Dynamic changes in vascular tone are determined, in large part, by the endothelial nitric oxide synthase (eNOS)/nitric oxide (NO)/cGMP axis. We used pharmacological gain of function of the eNOS/NO/cGMP axis in diet-induced obese (DIO) mice and reduced function in lean mice to test the hypothesis that functionality of this vascular control mechanism parallels the benefits of an exercise training regimen. DIO mice have 50% lower exercise capacity (P < 0.0001) than lean mice and were used for pharmacological gain of function. The phosphodiesterase-5a (PDE-5a) inhibitor, sildenafil, increases cGMP and was administered to DIO mice daily. In sedentary mice, neither acute nor chronic sildenafil improves exercise capacity. In contrast, chronic sildenafil synergizes with exercise training to improve performance during an incremental exercise test. Improved exercise performance was accompanied by a 40% increase in basal skeletal muscle capillary flow velocity and ∼20% increase in plasma-perfused capillary density measured via intravital microscopy. Loss of function was tested in lean mice hemizygous for endothelial cell (EC) specific eNOS creating an EC-eNOS knockdown (KD). EC-eNOS KD decreases capillary density and exercise tolerance in sedentary mice; however, it did not prevent exercise-training-induced improvements in endurance capacity. These data show that 1) increasing cGMP with sildenafil enhances microcirculatory function and exercise work tolerance that results from training; 2) eNOS KD does not prevent the microcirculatory or improvements in exercise tolerance with training. PDE-5a inhibitors combined with physical exercise are a potential mechanism for improving ambulation in patients with circulatory limitations.NEW & NOTEWORTHY This study used pharmacological gain-of-function and genetic loss-of-function approaches to test the hypothesis that the eNOS/NO/cGMP axis is central to exercise training adaptations in microcirculatory function and exercise capacity. Chronic but not acute treatment with the PDE5 inhibitor, sildenafil, synergizes with exercise training to improve performance with incremental exercise in obese mice; whereas endothelium-specific knockdown in eNOS does not blunt the microcirculatory adaptations and improvements in exercise tolerance with training.