Modulation of endothelial cell phenotype by physical activity: impact on obesity-related endothelial dysfunction.

Increased levels of physical activity are associated with reduced cardiovascular disease (CVD) risk and mortality in obesity and diabetes. Available evidence suggests that local factors, including local hemodynamics, account for a significant portion of this CVD protection, and numerous studies have interrogated the therapeutic benefit of physical activity/exercise training in CVD. Less well established is whether basal differences in endothelial cell phenotype between/among vasculatures related to muscle recruitment patterns during activity may account for reports of nonuniform development of endothelial dysfunction in obesity. This is the focus of this review. We highlight recent work exploring the vulnerability of two distinct vasculatures with established differences in endothelial cell phenotype. Specifically, based largely on dramatic differences in underlying hemodynamics, arteries perfusing soleus muscle (slow-twitch muscle fibers) and those perfusing gastrocnemius muscle (fast-twitch muscle fibers) in the rat exhibit an exercise training-like versus an untrained endothelial cell phenotype, respectively. In the context of obesity, therefore, arteries to soleus muscle exhibit protection from endothelial dysfunction compared with vulnerable arteries to gastrocnemius muscle. This disparate vulnerability is consistent with numerous animal and human studies, demonstrating increased skeletal muscle blood flow heterogeneity in obesity coincident with reduced muscle function and exercise intolerance. Mechanistically, we highlight emerging areas of inquiry exploring novel aspects of hemodynamic-sensitive signaling in endothelial cells and the time course of physical activity-associated endothelial adaptations. Lastly, further exploration needs to consider the impact of endothelial heterogeneity on the development of endothelial dysfunction because endothelial dysfunction independently predicts CVD events.