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

Area of Science:

• Cardiovascular Physiology
• Exercise Science
• Pharmacology

Background:

• Impaired microvascular function, linked to atherosclerosis and type 2 diabetes, diminishes exercise capacity.
• The endothelial nitric oxide synthase (eNOS)/nitric oxide (NO)/cGMP pathway is crucial for regulating vascular tone and microcirculation.
• Understanding this pathway's role in exercise adaptations is key for improving physical function.

Purpose of the Study:

• To investigate if enhancing the eNOS/NO/cGMP axis with sildenafil synergizes with exercise training to improve exercise capacity and microcirculatory function in diet-induced obese (DIO) mice.
• To determine if reducing eNOS function in lean mice affects exercise training adaptations.

Main Methods:

• Pharmacological gain-of-function: DIO mice received daily sildenafil (a PDE-5a inhibitor) or placebo, with or without chronic exercise training.
• Genetic loss-of-function: Lean mice with endothelial cell-specific eNOS knockdown (KD) were subjected to exercise training.
• Measurements included exercise capacity, skeletal muscle capillary flow velocity, and plasma-perfused capillary density via intravital microscopy.

Main Results:

• Chronic sildenafil treatment synergized with exercise training to significantly improve exercise performance in DIO mice.
• This improvement was associated with increased skeletal muscle capillary flow velocity and plasma-perfused capillary density.
• Endothelial cell eNOS knockdown in lean mice did not prevent exercise-training-induced improvements in endurance capacity or microcirculation.

Conclusions:

• Chronic administration of sildenafil enhances microcirculatory function and exercise tolerance in conjunction with training.
• The eNOS/NO/cGMP pathway is important, but its complete abrogation does not prevent exercise training-induced microcirculatory adaptations.
• Combining PDE-5a inhibitors with physical exercise presents a potential strategy for improving ambulation in patients with circulatory limitations.