Molecular plasticity of vascular wall during N-G-nitro-L-arginine methyl ester-induced hypertension - Modulation of proinflammatory signals

It has previously been reported that hypertension induced by the chronic bl ockade of NO production is characterized by a proinflammatory phenotype of the arterial wall associated with a periarterial accumulation of inflammato ry cells. In the present study, the cellular and molecular mechanisms invol ved in the luminal and perivascular accumulation of inflammatory cells were evaluated in the aortas of N-G-nitro-L-arginine methyl ester (L-NAME)-trea ted rats. Because the medial layer remains intact, putative markers of the resistance of the vascular wall to cell migration and to oxidative stress w ere also explored. For this purpose, monocyte adhesion, cytokine expression , superoxide anion production, and nuclear factor-kappa B (NF-kappa B) acti vation were assessed in the aortas of L-NAME-treated rats. Expressions of t issue inhibitor of metalloproteinases-1 (TIMP-1) and heme oxygenase-1 (HO-1 ) in the aortic wall were also studied as possible markers of such resistan ce. Chronic blockade of NO production increased ex vivo monocyte adhesion t o the endothelium, increased the production of superoxide anions, and activ ated the NF-kappa B system. In concert with this modification of the redox state of the vascular wall in L-NAME-treated rats, the expression of proinf lammatory cytokines interleukin-6, monocyte chemoattractant protein-1, and macrophage colony-stimulating factor was increased. In parallel, expression s of both TIMP-1 and HO-1 were increased. All these changes were prevented by treatment with an angiotensin-converting enzyme inhibitor (Zofenopril). Hypertension associated with a proinflammatory phenotype of the vascular wa ll induced by blockade of NO production could be due to an increase in oxid ative stress, which, in turn, activates the NF-kappa B system and increases gene expression. In parallel, the arterial wall overexpresses factors such as TIMP-1 and HO-1, which could participate in the resistance to cell migr ation and oxidative stress.