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inflammation observed in autonomic areas. Indeed, several experimental studies
revealed reduced end-organ injuries in trained hypertensive animals. For instance,
8 weeks of aerobic training attenuate myocardial collagen accumulation and fibrosis
in adult [ 69 , 90 ] and aged SHR [ 22 ], contributing to restore the depressed diastolic
function. Also, training decreases cytosolic calcium concentration, attenuates
calcineurin- NFAT pathway and decreases left ventricle wall thickness, therefore
correcting the deleterious hypertension-induced cardiac remodeling [ 69 , 90 ].
The functional benefits of exercise training are also associated to the decrease of
either NADPH oxidase-generated superoxide, NF-kB activity and pro-inflamma-
tory cytokines expression in the heart, kidney and brain, thus contributing to reduce
the local end-organ damage in hypertensive animals [ 46 , 69 , 91 ].
3 Mechanisms Contributing to Deleterious Remodeling
of Peripheral Circulation
Drawing up the pathophysiological picture of hypertension, vascular deleterious
remodeling contributes to establishment and maintenance of essential or primary
hypertension [ 92 , 93 ]. Vessels’ adaptations in hypertensive subjects occur in differ-
ent segments of the vascular tree: stiffness in conducting and muscular arteries,
marked hypertrophy in small arteries and arterioles and capillary/small veins rar-
efaction in the microcirculation. Experimental studies demonstrated that increased
arterial stiffness (defined as the decreased capacity of the vascular wall to convert
kinetic energy in elastic potential energy) precedes the onset of blood pressure ele-
vation in salt-sensitive [ 94 ], essential [ 95 ] and high fat diet hypertension [ 96 ]. Two
well-characterized mechanisms promote arterial stiffness in hypertension: reduc-
tion of fenestrae’s density in the internal elastic lamina and disorganization of the
vascular tissue. Juvenile pre-hypertensive SHRs (30 days-old) already exhibit
decreased fenestrae area and elastin deposition when compared to age-matched
Wistar-Kyoto rats. These two structural factors promote a left shift of stress x strain
curve, a mechanical abnormality that increases wall stiffness in conductance vessels
of the juvenile SHRs [ 97 , 98 ].
Vascular tissue disorganization results from cellular/molecular dysfunctions inendothelial and smooth muscle cells. In hypertensive subjects, endothelium pres-
ents marked imbalances between vasodilator and vasoconstrictor factors, antioxi-
dant enzymes and pro-inflammatory agents. The major endothelial molecular
mediator, the nitric oxide (NO), is produced in a reaction catalyzed by endothelial
NO synthase (eNOS). This reaction converts L-arginine into L-citrulline, releasing
nitric oxide, NADP+ and a water molecule. Tetrahydrobiopterin (BH4) is a impor-
tant co-factor for nitric oxide production. In a hypertensive endothelial environ-
ment, BH4 is oxidized to dihydrobiopterin (BH2, a biologically inactive form) by
the abundant reactive oxygen species, such as superoxide and hydrogen peroxide. In
the absence of BH4, eNOS still releases NO, but also superoxide, which reacts with
NO producing the peroxynitrite (eNOS uncoupling). In addition to BH4 oxidation,
G.S. Masson and L.C. Michelini