Rôle du monoxyde d'azote dans la calcification vasculaire et la rigidité artérielle dans un modèle d'hypertension systolique isolée

Isolated systolic hypertension (ISH) is the result of complex changes in the vascular wall and consequently the increase of arterial stiffness.  These modifications occur mainly in conductance arteries, like the aorta, and are associated with aging.  The fragmentation of elastic fibers, calcification (elastocalcinosis), and fibrosis are major changes with age.  In addition to these changes in the extracellular matrix, vascular aging also induces vascular cell wall modifications. These include decreased production of nitric oxide (NO) by endothelial cells, which induces endothelial dysfunction, and the production of matrix and bone proteins by vascular smooth muscle cells (VSMCs).  Located between the blood and VSMCs, the endothelium controls vascular tone by secreting various vasoactive factors.  These factors interact with each other to maintain the hemodynamic of the vascular system.  Among these factors, the vasoconstrictor endothelin (ET) and the vasodilator NO.  The latter has been shown to block ET production via a cyclic guanosine monophosphates-(cGMP) dependent mechanism, whereas ET has been implicated in arterial calcification. Therefore, NO might be involved in the modulation of elastocalcinosis and arterial stiffness by inhibiting ET and modifying the vascular wall composition.  This effect of NO could offer interesting therapeutic potential for ISH.  To evaluate the implication of NO in the vascular calcification and arterial stiffness, an animal model of ISH was used.  This model of elastocalcinosis is based on the inhibition of the maturation of the anti-calcific protein, matrix Gla protein (MGP), by warfarin (WVK model).  To gain insight into the physiological role of endogenous NO in the initiation and progression of elastocalcinosis, its production was inhibited by the administration of L-NAME.  Interestingly, elastocalcinosis was prevented by L-NG-nitroarginine methyl ester (L-NAME) administration without any modifications of the pulse wave velocity (PWV) during the initiation of the calcification processes.  After the L-NAME treatment, the expression of inducible NO synthase (iNOS) was decreased, whereas upon treatment with warfarin alone the expression of iNOS was increased, which could be implicated in vascular calcification and arterial stiffness.  In addition, endothelial NO synthase (eNOS) seems to be implicated in this process as its expression was also increased upon WVK treatment.  This increase could be beneficial to limit elastocalcinosis, whereas the increase in iNOS expression could be harmful.  L-NAME administration during the progression of calcification increased elastocalcinosis and PWV.  In an endothelial dysfunction context, ET has been shown to be involved in the amplification process of vascular calcification causing an increase in arterial stiffness.  As NO limits the progression of calcification and consequently arterial stiffness, endogenous NO seems to be protective in the aorta.  The efficacy of exogenous modulation of the NO pathway in the WVK model was studied upon administration of the NO donor, sinitrodil, or the phosphodiesterase type 5 inhibitor (PDE5), tadalafil.  The exogenous modulation of the NO pathway seemed to be beneficial for arterial stiffness, but only in an acute manner.  Indeed, sinitrodil modified the acute stiffness in the aorta potentially by vascular tone modulation, without having any effect on vascular wall composition.  Since endothelial function was not affected upon WVK model, endogenous NO concentrations seem to be optimal.  Thus, exogenous NO potentially caused an increase of elastocalcinosis by inducing tolerance to NO.  As well as sinitrodil, tadalafil modulated the arterial stiffness in an acute manner without modifying the composition of the vascular wall.  Broadly, these studies provide evidence that endogenous NO can limit ISH development, suggesting that endothelial dysfunction, as observed in aging, has a negative impact on this pathology.

Keyphrases: nitric oxide, aortic stiffness, phosphodiesterase inhibitors, NO donors, vascular calcification, isolated systolic hypertension, pulse wave velocity