Effects of exercise on nitric oxide synthase (NOS)
Regular physical exercise has been shown to improve endothelium-dependent vasodilatation in both experimental models and humans. One of the most important molecular consequences of exercise is the absolute increase of vascular nitric oxide (NO) concentration. The production of NO is catalyzed by NOS. Three isoforms of NOS, termed neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) have been recognized. A large number of studies (Cortese-Krott, Kulakov et al. 2014) demonstrated that the presence of iNOS is minimal under physiological conditions. Increase in the production of NO by iNOS is observed in response to the inflammation. Inflammation-induced iNOS expression in the endothelium may contribute to vascular dysfunction by limiting the availability of tetrahydrobiopterin (BH4) for eNOS. The production of iNOS within vascular smooth muscle cells following exposure to pro-inflammatory cytokines is a major cause of the hypotension, cardiodepression and vascular hyporeactivity in septic shock. The nNOS is a soluble cytosolic isoform which found in neuronal- endothelial and epithelial cells. Vascular injury induces expression of nNOS in the intima and the medial smooth muscle cells and selective inhibition of this isoform increases the responses to various vasoconstrictors, suppresses the production of cyclic guanosine monophosphate (cGMP) and damages neointimal formation. Similarly to nNOS, eNOS requires calcium ions to produce NO. The activity of eNOS and thus the production of NO can be initiated/enhanced by several stimuli including shear stress, acetylcholine, bradykinin, histamine and 17β-estradiol in both calcium-dependent- and independent pathways. Endothelial NOS is the major isoform regulating vascular function via soluble guanylate cyclase (sGC) in the vascular smooth cells to induce cGMP formation. Exercise-induced upregulation of eNOS expression are mediated by intermittent increases of laminar shear stress associated with increased cardiac output during physical exertion. Shear stress is the product of all the perpendicular and parallel flow- mediated forces on endothelial cells. On the luminal side of endothelial cells, direct signal can occur through deformation of the glycocalyx which activates the calcium ion channels, phospholipase activity leading to calcium signalling, prostaglandin I2 (PGI2)- release, and cyclic adenosine monophosphate (cAMP)-mediated smooth-muscle-cell relaxation. VEGF receptor 2 (VEGFR2) can activate PI3K to phosphorylate Akt and induce AKT-mediated eNOS phosphorylation, leading to higher NO production. Akt indicates protein kinase B; AA, arachidonic acid; VEGF, vascular endothelial growth factor. Increased NO synthesis secondary to amplified shear stress induces extracellular superoxide dismutase (SOD) expression in a positive feedback manner so as to inhibit the degradation of NO by ROS (Gielen, Schuler et al. 2010) (Figure 2).
Figure 2. The effect of exercise-induced shear stress on vascular tone
The endothelium- dependent vasodilator effect of exercise training has been investigated in both animal models and humans. Tanaka et al. examined the regulation of NO on acute adaptations to exercise. They found that acute exercise improved endothelium-dependent vasodilation in rat aorta by increased eNOS activation. These results shows that one bout of moderate aerobic exercise improves endothelial function by increasing NO bioavailability, while superoxide and hydrogen peroxide are generated in a controlled mode (Tanaka, Bechara et al. 2015). In another model, Roque et al. demonstrated that 12 weeks of aerobic exercise improved endothelial function and vascular stiffness in coronary and mesenteric arteries in spontaneously hypertensive rats (Roque, Briones et al. 2013).