Vascular Effects of Exercise Training in CKD: Current Evidence and Pathophysiological Mechanisms

Training-induced increase in NO bioavailability in CKD. (A) NO is synthesized from l-arginine by eNOS after agonist occupation (merely calcium-dependent) or shear stress (merely calcium-independent). Other than its role as a relaxing factor, NO inhibits leukocyte adhesion, platelet aggregation, and inflammation and acts as an important liberator of stem and progenitor cells in the vascular zone of the bone marrow (35). eNOS is predominantly present in caveolae, which are flask-shape invaginations of the luminal endothelial plasma membrane (36). In basal conditions, eNOS is maintained in an inactive state in caveolae by interaction with caveolins. Increase in intracellular calcium in response to agonist stimulation leads to the disruption of the caveolin–eNOS interaction by calcium-bound calmodulin; hsp90 consecutively binds eNOS and favors the recruitment of PKB/Akt, leading to eNOS phosphorylation. Activation of Akt results from the activation of signaling pathways, including the stimulation of PI3K in response to a variety of agonists and shear stress (mechanotransducers), the latter being the most potent stimulus for continuous eNOS activity (37). (B) NO bioavailability in CKD is reduced because of a number of mechanisms. First, eNOS activity can be reduced as a result of increased inhibition (increased ADMA levels) and decreased activation (less PKB/Akt expression and increase in caveolin-1 expression) (38–41). Second, there is an increase in ROS-mediated breakdown of NO as a result of increased oxidative stress. The latter results from increased activation of ROS-generating enzymes, such as xanthine oxidase, NAD(P)H-oxidase, and eNOS uncoupling, for example, as a result of BH4 deficiency or increased ADMA levels as well as a lack of efficient antioxidative defense mechanisms. After interaction with NO, superoxide anion forms highly toxic nitrogen derivatives, such as peroxynitrite (which is cytotoxic) and increases platelet aggregation and vasoconstriction. (C) Green-shaded areas represent evidence from animal and human studies in cardiovascular disease. When framed, evidence is available for patients in CKD. As we know from studies in patients with stable coronary artery disease, most ET effects on the vascular endothelium are mediated by increases in shear stress, which results in higher NO production. An increase in eNOS activity occurs within seconds and implicates cytosolic calcium and eNOS phosphorylation. Later increases in transcription and eNOS mRNA stability allow maintenance of an increased NO production when the stimulus is prolonged. In addition to eNOS activation, ET results in more efficient antioxidative defense mechanisms (e.g., by reducing ROS production [reduction in NAD(P)H expression, less eNOS uncoupling, etc.] and increasing the expression of antioxidative enzymes and ROS scavengers [e.g., glutathione]) (9,55,56). As such, ROS-mediated breakdown of NO is prevented. A decrease in ADMA levels could contribute to both an increase in eNOS activity and prevention of eNOS uncoupling (44). ADMA, asymmetric dimethylarginine; BH4, (6R)-5,6,7,8-tetrahydro-L-biopterin; CaM, calmodulin; cav, caveolin; cGMP, cyclic guanosine monophosphate; DDAH, dimethylarginine dimethylaminohydrolase; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; GC, guanylyl cyclase; GTP, guanosine triphosphate; hsp90, heat shock protein 90; NO, nitric oxide; O2°, superoxide anion; ONOO°, peroxynitrite; P, phosphorus; PI3K, phosphatidylinositol 3-kinase; PKB/Akt, protein kinase B; ROS, reactive oxygen species; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cells.