Different Involvement of Extracellular Matrix Components in Small and Large Arteries During Chronic NO Synthase Inhibition

Abstract

Abstract-In essential hypertension, conduit arteries present hypertrophic remodeling (increased cross-sectional area), whereas small arteries undergo eutrophic remodeling. The involvement of matrix metalloproteinases (MMPs) and de-adhesion proteins, such as tenascin-C and thrombospondin, has been relatively well characterized in large artery remodeling, but their contribution is not known in small artery remodeling. Rats received N -nitro-L-arginine methyl ester (L-NAME; 50 mg/kg per day) in their drinking water on days 1, 3, 7, 14, and 28. Arterial MMP-2 activity was measured by ELISA, whereas levels of tenascin-C and thrombospondin were assessed by Western blotting. To determine the involvement of MMPs, additional L-NAME rats received the nonselective MMP inhibitor doxycycline (30 mg/kg per day) on days 7, 14, and 28. Already, at day 1, pressure was elevated. Media/lumen ratio of mesenteric arteries and the aorta increased gradually to reach significance at 28 days. However, the cross-sectional area increased only in the aorta, confirming the heterogeneous remodeling process. In small arteries, MMP-2 activity increased after 7 and 14 days of treatment and returned to baseline at 28 days, whereas the elevation was more progressive but sustained in the aorta. The level of thrombospondin paralleled that of MMP-2 in small arteries, whereas tenascin-C levels declined rapidly and stayed below control values. Doxycycline blunted large artery remodeling but had no influence on the development of eutrophic remodeling despite elevation of MMP-2 activity in the process. Thus, in contrast to large artery hypertrophic remodeling, in which the contributions of cellular de-adhesion and matrix breakdown is manifest, the contribution of MMPs in eutrophic remodeling appears less crucial. Key Words: nitric oxide synthase Ⅲ arteries V ascular remodeling is considered an adaptive response to elevation of arterial pressure to normalize the wall tension. In essential hypertension, large artery remodeling is characterized by an increase in media thickness-lumen diameter (M/L) ratio and cross-sectional area (CSA). This augmentation of media mass, or hypertrophic remodeling, is explained by changes in size or number of vascular smooth muscle cells (VSMCs) and matrix collagen deposition. 1 In resistance arteries (diameter Ͻ300 m), essential hypertension is associated with a reduced lumen and increased M/L ratio but without CSA increase, producing a type of remodeling designated as inward eutrophic remodeling. 2 To explain this different response between large and small arteries, it is suggested that small arteries are not submitted to an augmented wall stress because they are initially constricted. 3-5 Thus, we hypothesized that inward eutrophic remodeling, which appears as a fixed form of vasoconstriction, could proceed through specific modifications of VSMC-matrix interactions.As in essential hypertension, chronic inhibition of NO synthesis with the L-arginine analogue N -nitro-L-arginine methyl ester (L-NAME) produces hypertrophic re...

Circulating matrix metalloproteinases and their endogenous inhibitors in patients with erectile dysfunction

“…12,13,[28][29][30] While there is evidence that MMPs in erectile dysfunction JJ Muniz et al patients with ED are more likely to have the vascular alterations commonly found in cardiovascular diseases, 2,4-9 especially among diabetics, 4-6,10,11 our findings showed similar net MMP-2 and MMP-9 activities in ED patients and in healthy controls, thus suggesting that these enzymes may not be involved in ED. Importantly, MMPs levels were carefully assessed by two independent, different techniques in the present study, thus minimizing the probability of analytical limitations.…”

“…Imbalanced MMPs activities have been implicated in many clinical cardiovascular diseases, [12][13][14][15][16][17][18]27 and the use of MMPs inhibitors has been suggested as a relevant pharmacological target, especially to prevent the vascular alterations associated with these conditions. 12,13,[28][29][30] While there is evidence that MMPs in erectile dysfunction JJ Muniz et al patients with ED are more likely to have the vascular alterations commonly found in cardiovascular diseases, 2,4-9 especially among diabetics, 4-6,10,11 our findings showed similar net MMP-2 and MMP-9 activities in ED patients and in healthy controls, thus suggesting that these enzymes may not be involved in ED.…”

“…2,9 Moreover, ED is very common among men with diabetes mellitus (DM), [4][5][6]10,11 in whom the prevalence has been reported to vary from 20-71%. 10 Recent studies have implicated matrix metalloproteinases (MMPs) as key players in the functional and structural cardiovascular alterations associated with hypertension [12][13][14][15] and with other cardiovascular diseases. 16,17 Although MMPs are widely known to degrade the components of the extracellular matrix, they also have many other roles that are now being widely studied, especially in the cardiovascular system.…”

“…Therefore, we studied the circulating MMP-2 and MMP-9 levels (which are the very relevant MMPs in the pathogenesis of cardiovascular diseases [12][13][14][15][16][17][18] ) in ED patients with or without DM, and in healthy controls. In addition, we have also assessed the circulating levels of major MMPs endogenous inhibitors, the tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2.…”

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

“…Beyond cell culture, limiting NO for 28 days in male rats by daily feeding of L-NAME in the drinking water was associated with increased TSP1 protein expression in distal mesenteric arteries and elevated blood pressure (17). In a small clinical study, 4 weeks of aerobic training in healthy young men was associated with increased eNOS protein expression in vastus lateralis muscle samples.…”