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