Differential Involvement of Matrix Degrading Enzymes in Antihypertensive-Drug Induced Vascular Structural Changes

Shoichet, Martin J; Hale, Taben M.; Graham, Charles H.; Bushfield, Terri L; Adams, Michael

doi:10.1016/j.carpath.2004.03.362

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“…Indeed, a very recent study (abstract form) has shown that during reverse vascular remodeling induced by antihypertensive therapy, u-PA activity was more important than MMP-2 activity. 40 Because doxycycline does not inhibit u-PA, our study did not evaluate this possibility.…”

Section: Perspectivesmentioning

confidence: 97%

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

et al. 2005

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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...

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Section: Perspectivesmentioning

confidence: 97%