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3.1 Exercise Training in the Amelioration of Peripheral
Circulatory Deficits
The peripheral vascular adaptations are the best well-documented exercise training
benefits. Old experimental studies have already identified the improvement of both
endothelial function in conductance vessels and capillary density in a variety of
tissues [ 109 , 110 ]. The main mechanism suggested to explain training-induced vas-
cular benefits is the shear stress [ 111 , 112 ]. During an acute bout of exercise, car-
diac output raises in order to achieve the increased metabolic demand. As a
consequence, the augmented frictional force generated by the increased blood flow
triggers calcium influx from extracellular into the cytosol of endothelial cells
through mechanosensing ion channels. Mechanical deformation of endothelial cells
also increases the calcium flux from endoplasmatic reticulum to cytosol. Calcium
not only is a required cofactor for eNOS catalytic effect, but also triggers calcium-
calmodulin kinase activity, which phosphorylates eNOS and causes NO release. A
further increase in cytosolic calcium is mediated through integrins’ activation by the
shear stress, which activates phosphatidylinositide 3-kinases/protein kinase B
(PI3K/Akt) signaling pathway [ 113 ]. This signaling pathway directly phosphory-
lates eNOS, increasing NO production.
NO exhibits a wide variety of cellular/molecular actions, many of them modulat-ing the benefic vascular remodeling induced by exercise training. NO diffuses from
the endothelial membrane to smooth muscle cells, where it activates soluble guanyl-
ate cyclase increasing local cGMP levels. cGMP activates cGMP-dependent kinases
that decrease cytosolic calcium, inducing the vasodilation. In addition to the direct
vasodilator effect, NO attenuates NADPH oxidase activity through S-nitrosylation
of p47phox. NO, via S-nitrosylation, also elicits the inhibition of the highly revers-
ible protein tyrosine phosphatases protecting them from the irreversible cysteine
oxidation and inactivation [ 114 ]. Taken together, these data indicate that NO inhib-
its the production of reactive oxygen species by the NADPH oxidase and induces
potent vasodilation.
During the acute bout of exercise, endothelial cells produce reactive oxygen spe-cies, which oxidize a critical cysteine of Keap-1 (a Nrf2 repressor protein) causing
the translocation of Nrf2 to the cellular nucleus where it binds to ARE (antioxidant
responsive element) inducing gene expression of several antioxidant enzymes, such
as heme oxygenase-1 and thioredoxin reductase-1 [ 115 – 117 ]. In the thoracic aorta
and small mesenteric arteries training attenuates thromboxane A2-induced vasocon-
striction and increased the vasodilation to acetylcholine in SHRs [ 118 , 119 ] and
obesity-induced hypertension [ 120 ]. Together, these mechanisms improve
endothelial- induced reduction of the vasomotor tonus in arteries. Exercise intensity
is shown to affect vascular response to training. Battault and colleagues [ 121 ] com-
pared moderate vs. high intensity (55% vs. 80% of maximal exercise capacity)
showing that high intensity induces oxidative stress (and the consequent eNOS
G.S. Masson and L.C. Michelini