Nitric oxide synthase 3-dependent vascular remodeling and circulatory dysfunction in cirrhosis - PubMed (original) (raw)

Nitric oxide synthase 3-dependent vascular remodeling and circulatory dysfunction in cirrhosis

Guillermo Fernández-Varo et al. Am J Pathol. 2003 Jun.

Abstract

Vascular remodeling is an active process that consists in important modifications in the vessel wall. Endothelium-derived nitric oxide (NO) plays a major role in this phenomenon. We assessed wall thickness (WT), total wall area (TWA), lumen diameter, and total nuclei number/cross-section (TN) in cirrhotic rats with ascites and in control rats. A second group of cirrhotic rats received the NO synthesis inhibitor, L-NAME, or vehicle daily for 11 weeks and systemic hemodynamics, arterial compliance, aortic NO synthase 3 (NOS3) protein expression, and vascular morphology were analyzed. Cirrhotic vessels showed a significant reduction in WT, TWA, and TN as compared to control vessels. Long-term inhibition of NOS activity in cirrhotic rats resulted in a significant increase in WT, TWA, and TN as compared to cirrhotic rats receiving vehicle. NOS3 protein abundance was higher in aortic vessels of nontreated cirrhotic animals than in controls. This difference was abolished by chronic treatment with L-NAME. NOS inhibition in cirrhotic rats resulted in higher arterial pressure and peripheral resistance and lower arterial compliance than cirrhotic rats receiving vehicle. Therefore, vascular remodeling in cirrhosis with ascites is a generalized process with significant functional consequences that can be negatively modulated by long-term inhibition of NOS activity.

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Figures

Figure 1.

Figure 1.

Photomicrographs of representative cross sections of thoracic and abdominal aorta, and mesenteric and renal arteries from a control rat (A, C, E, and G, respectively) and a cirrhotic rat with ascites (B, D, F, and H, respectively). Note the marked reduction in WT and the diminution in the number of nuclei in the cirrhotic vessel (H&E staining; original magnifications, ×200).

Figure 2.

Figure 2.

WT, LD, TWA, and WT/LD ratio in control rats and in cirrhotic rats with ascites. THORAC, thoracic aorta; ABDOM, abdominal aorta; MES, mesenteric artery; REN, renal artery. Data are mean ± SE; n = 6 rats per group.

Figure 3.

Figure 3.

WT, LD, TWA, and WT/LD ratio in cirrhotic rats receiving vehicle or chronically treated with L-NAME (0.5 mg/kg/day). THORAC, thoracic aorta; ABDOM, abdominal aorta; MES, mesenteric artery; REN, renal artery. Data are mean ± SE; n = 7 rats per group.

Figure 4.

Figure 4.

Aortic cGMP concentration in control and cirrhotic rats receiving vehicle or chronically treated with L-NAME (0.5 mg/kg/day). Thoracic aortas were individually homogenized and the concentration of cGMP was measured in the acetylated extracts by radioimmunoassay. Eight cirrhotic and 12 control rats were studied, half of the animals in each group being treated with L-NAME. Data are mean ± SE.

Figure 5.

Figure 5.

Representative Western blot of total NOS3 (A) and phospho-NOS3 (p-NOS3) (B) protein in thoracic aorta of control and cirrhotic rats receiving vehicle or chronically treated with L-NAME (0.5 mg/kg/day). Protein extracts were prepared as described in Material and Methods and 40 μg (total NOS3) or 80 μg (p-NOS3) of protein were loaded per lane. Ten μg of human vein endothelial cell (HUVEC) lysate or stimulated bovine aortic endothelial cells (BAEC) were used as a positive control.

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