**6. Possible mechanisms of the effect of sodium intake reduction on arterial stiffness**

Animal studies of hypertension demonstrate that elevated salt consumption can increase arterial stiffness and this effect is independent of BP as reviewed by Safar et al. [52]. On the other hand, reduced dietary sodium has been shown to lower arterial stiffness in humans with hypertension [27, 60]. Cross-sectional studies in humans have provided evidence of an independent effect of salt on arterial stiffness.

Experimental studies on animal models did show that changes in sodium intake have effects on arterial structure and function independent of blood pressure [18, 61]. Studies carried out in normotensive rats have shown that these changes might be associated with increased production of transforming growth factor-beta 1 (TGF-β1), decreased endothelial nitric oxide synthase expression, and reduced bioavailability of endothelial nitric oxide induced by a high-salt diet [18, 37, 61–63]. TGF-β is a family of three pleiotropic growth factors that have complex effects on cell growth and differentiation and organ development, but they are particularly important in the expression of extracellular matrix proteins and vascular and renal fibrosis promotion in a variety of disease states [64]. The TGF-β1 is considered the most important mammalian TGF-β family member synthesized by many cell types including endothelium. It is secreted by endothelium acting, basically, on adjacent vascular smooth muscle and seems to be involved in blood pressure regulation [37].

The reduction of salt intake in the diet can affect the vascular properties by reducing the production of TGF-β. The study by Grigorova et al. [37] has investigated whether high salt intake stimulates the production of MBG, an endogenous steroidal Na+ /K+ -ATPase ligand which activates transforming growth factor-beta pro-fibrotic signaling in young normotensive rats and whether these changes can be reversed by reducing salt to a normal salt level. Their data have suggested that a decrease in salt consumption could help to restore vascular properties such as the aortic elasticity and lower the risk of cardiovascular disease by reducing the production of the pro-fibrotic factor MBG.

The local renin-angiotensin-aldosterone system (RAAS) is believed to be one of the most important mediators of vascular wall elasticity at the heart, vessels, and kidneys [19, 65]. At the cardiovascular system, high sodium intake increases the AT1 receptor expression and promotes vascular damage [19]. Evidence from experimental studies has shown that there was a decrease in aortic collagen accumulation and improvement of vascular, cardiac, and renal function and an AT1 receptor blocker during the high salt intake diet [12, 19, 66]. Additionally, high sodium intake has been reported to increase the vascular angiotensin-converting enzyme levels, which opposes to the effects of concomitant renin suppression [67]. Studies carried out in hypertensive subjects found gene polymorphisms of aldosterone synthase enzyme and AT1 receptor that was significantly associated with higher PWV [68, 69].

Stocker et al. [70] in their study discussing the recent evidence to support the role of plasma or cerebrospinal fluid hypernatremia as a key mediator of sympathoexcitation and elevated blood pressure have found that both experimental and clinical studies suggested that a high dietary salt increases plasma and cerebrospinal fluid sodium concentration. Sodium concentration variation modulates the sympathetic neurons in rostral medulla by activating the osmoreceptors in the rostral nervous system that is responsible for the tone of basal sympathetic vasomotor [70–73].

The evidence also point outs the high dietary salt intake is one of the most important factors to the activation of the sympathetic nervous system, which is one of the main contributing factors for the pathogenesis of salt-sensitive hypertension [69, 74]. Although not well understood, it is proposed that increased salt intake causes salt retention and raises plasma sodium chloride concentrations, which activates sodium/osmoreceptors to trigger sympathoexcitation [75]. Some studies have suggested that vascular properties such as arterial compliance may be affected by sympathetic nervous activity, independently of its effects on BP [76]. Therefore, the reduction of salt intake decreases the excitability of the sympathetic nervous system and interferes with its effects on vascular properties reducing the arterial stiffness.
