Role of Matrix Metalloproteinases in Blood Flow–Induced Arterial Enlargement

Abstract

Abstract-Tears in the internal elastic lamina (IEL) can be observed after chronic increases in arterial blood flow, suggesting a potential role for matrix metalloproteinases (MMPs) in flow-induced vascular remodeling. We undertook to study this phenomenon by constructing an arteriovenous fistula (AVF) between the left common carotid artery (CCA) and the external jugular vein in rabbits. The diameter of the flow-loaded left CCA increased by 13.6Ϯ1.8% by day 3 after construction of the AVF compared with the right CCA (nϭ4, PϽ0.01) and by 40.7Ϯ7.5% by day-15 (nϭ10, PϽ0.0001). Increased CCA diameter also coincided with IEL fragmentation. Three days after construction of the AVF, gelatin zymography of protein extracts from left CCAs of untreated rabbits showed a significant increase in the 62-kDa (active MMP-2) activity and the appearance of a lytic band at 92 kDa (pro-MMP-9). In further experiments, MMP activity was inhibited by treatment with doxycycline (DOX) or BB-94, a specific MMP inhibitor. The increase in the 62-kDa gelatinolytic band was abolished in DOX-and BB-94 -treated rabbits. The 92-kDa gelatinolytic band was also reduced in DOX-treated animals. Furthermore, both increased left CCA diameter and IEL fragmentation were abolished in DOX-and BB-94 -treated rabbits. To evaluate whether nitric oxide was involved in blood flow-induced MMP activation, the rabbits were treated with N G -nitro-L-arginine methyl ester to inhibit nitric oxide synthesis. MMP activities were significantly decreased in the left CCAs of Key Words: wall shear stress Ⅲ vascular remodeling Ⅲ matrix metalloproteinases C hronic increases in arterial blood flow elicit an adaptive response of the arterial wall, characterized by the reorganization of cellular and extracellular components and leading to arterial enlargement and a reduction in wall shear stress (WSS) to physiological baseline values. [1][2][3][4] There is evidence that the endothelium plays an essential role in this adaptive process. 3,5 In models of arteriovenous fistula (AVF), endothelial denudation abolishes arterial diameter growth, 3 and we have shown that chronic inhibition of nitric oxide (NO) production by N G -nitro-L-arginine methyl ester (L-NAME) treatment inhibits, at least partially, the adaptive WSS regulation in flow-loaded vessels. 4 However, the mechanisms by which the endothelium or endothelium-dependent NO operates to induce arterial wall remodeling are not understood. Interestingly, disruption of the extracellular matrix with tears of the internal elastic lamina (IEL) can be observed in this model, which suggests a potential role for matrix metalloproteinases (MMPs) in matrix digestion and reorganization, leading to arterial wall remodeling, 4,6 -11 and for NO in MMP activation. 12 This study was therefore designed to examine the effects of chronic in vivo inhibition of MMPs by treatment with BB-94, a specific MMP inhibitor, or doxycycline (DOX), on vascular remodeling of the common carotid artery (CCA) in a rabbit model of AVF. We also evaluated the effect...

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

“…Nonetheless, as a result of MMP inhibition, hypertrophic arterial remodeling was prevented. This is in line with studies showing prevention of blood flow-induced artery enlargement 31 and inhibition of several phases of intimal thickening after arterial injury. 32 In contrast to results obtained in large arteries, doxycycline treatment did not modify vascular remodeling in mesenteric arteries, suggesting that despite the increase of MMP-2 activity, this family of enzymes does not appear to be necessary for the eutrophic remodeling process to occur.…”

Inflammation in human cerebral aneurysms: pathogenesis, diagnostic imaging, genetics, and therapeutics

“…[5] Simultaneously, MMP activation has been found to facilitate flow-induced internal elastic lamina (IEL) fragmentation. [8] Similar IEL fragmentation is a feature commonly observed in atherosclerotic lesions. [9] Vascular smooth muscles cells (VSMCs), mainly found in the media layer, are recognized as major producers of matrix in the vessel wall.…”

Novel Paradigms for Dialysis Vascular Access

“…Key findings from this seminal study include the following (26): (1) HO-1 gene expression was markedly induced in HO-1 1 /1 mice compared with HO-1 2/2 mice, (2) strong HO-1 protein expression was present in vascular smooth muscle cells in HO-1 1/1 mice, (3) patency rates for AVF were significantly higher in HO-1 1/1 mice, with less vein wall thickness and increased luminal area compared with HO-1 2/2 mice at 3 weeks, and (4) expression of proinflammatory and prooxidant mediators, such as monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinases-2 and 9 (MMP-2 and MMP-9), was considerably greater in HO-1 2/2 than in HO-1 1/1 mice. MMPs play an important role in both inward (vasoconstriction) and outward vascular remodeling because they (1) are key enzymes that cause the breakdown of extracellular matrix proteins, such as collagen and elastin, to promote vasodilation (27,28) and (2) facilitate the proliferation and migration of smooth muscle cells and inflammatory cells, important processes in neointima hyperplasia development and vascular stenosis (29,30). The absence of HO-1 may lead to more prooxidant and proinflammatory effects from MMPs, as demonstrated in this study by Juncos et al (26).…”