Increased Plasmin and Serine Proteinase Activity During Flow-Induced Intimal Atrophy in Baboon PTFE Grafts

Kenagy, Richard D.; Fischer, Jens W.; Berceli, Scott A.; Hawkins, Suzanne; Wight, Thomas N.; Clowes, Alexander W.

doi:10.1161/hq0302.105376

Cited by 55 publications

(52 citation statements)

References 46 publications

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“…We have previously demonstrated increased serine protease (including plasmin) activity against versican in extracts of day 4 highflow intimas . Also, although MMPs do degrade versican (Halpert et al 1996;Kenagy et al 2002), there is no evidence of MMP activity against versican in these extracts suggesting that endogenous MMP inhibitors such as TIMP 1 block the MMPs in these extracts . By 14 days, a loss of proteoglycan staining in the graft intima is evident.…”

Section: Intimal Atrophymentioning

confidence: 87%

Accumulation and Loss of Extracellular Matrix During Shear Stress-mediated Intimal Growth and Regression in Baboon Vascular Grafts

Kenagy¹

2005

Journal of Histochemistry and Cytochemistry

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SUMMARYThe composition of extracellular matrix during growth and regression of the neointima was analyzed during healing in a baboon aorto-iliac polytetrafluoroethylene graft. Graft neointimal thickening can be modulated by altering blood flow by construction of downstream arteriovenous fistulas. Normal flow with normal shear stress induces neointimal thickening, whereas high flow with high shear stress upstream of a fistula induces regression of established neointima. The neointima formed under normal shear stress is enriched in hyaluronan and proteoglycans, particularly versican. On the other hand, the neointima near the graft material is enriched in collagen and biglycan. Neointimal regression in response to high shear stress is associated with a loss of proteoglycans as detected by histochemical staining. Immunostaining with an antibody against an ADAMTS cleavage neoepitope of versican increases after switching to high flow, although immunostaining for versican core protein is not appreciably changed by high flow. The present data demonstrate that the graft neointima is enriched with proteoglycans, particularly versican and hyaluronan, as well as collagen, and there is a differential distribution of each. Neointimal atrophy occurs with an apparent loss of proteoglycans and evidence of versican degradation. Keywords neointima; proteoglycans; shear stress; smooth muscle cells; versican INTIMAL HYPERPLASIA limits the long-term success of arterial grafting, bypass procedures, and stenting (Garratt et al. 1992;Hoffmann et al. 1996). The underlying mechanisms for this include increased smooth muscle cell (SMC) proliferation and migration in combination with extensive synthesis and deposition of extracellular matrix (ECM) by SMCs. The ECM plays an important role in the pathophysiology of neointimal thickening, because it contributes between 60% and 80% to the intimal mass in most forms of vascular lesions (Snow et al. 1990;Garratt et al. 1991;Strauss et al. 1994) and determines the mechanical characteristics of the neointima. ECM also influences the phenotype of neointimal SMC and, therefore, the function of SMCs (Raines 2000). Proteoglycans (versican, biglycan, and decorin) and hyaluronan are ECM molecules that accumulate in topographically distinct patterns within developing atherosclerotic and restenotic lesions [see reviews (Wight 1996;Toole et al. 2002)]. In a baboon model of polytetrafluroethylene (PTFE) graft neointimal growth and regression, the luminal surface of aorto-iliac PTFE grafts becomes fully endothelialized by transmural ingrowth of microvessels from the surrounding granulation tissue (Clowes et al. 1986). The extent of neointimal thickening depends on the rate of blood flow or shear stress. When grafts are allowed to heal under high blood flow or shear stress, grafts form a smaller neointima than those that heal under normal flow or shear stress (Kohler et al. 1991). If high shear stress grafts are returned to normal shear stress, the neointima begins to expand as the result of increased SMC prol...

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Section: Intimal Atrophymentioning

confidence: 87%

Accumulation and Loss of Extracellular Matrix During Shear Stress-mediated Intimal Growth and Regression in Baboon Vascular Grafts

Kenagy¹

2005

Journal of Histochemistry and Cytochemistry

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“…It should be noted that we decided to look specifically at MMP-2 because it has been shown in other work to be necessary for rat aortic SMC migration (33) and its expression is elevated under altered flow conditions (4,17). Palumbo et al (29) also reported that 15 h of 12 dyn/cm 2 SS downregulated MMP-2 but did not affect MMP-9 in bovine aortic SMCs.…”

Section: Discussionmentioning

confidence: 99%

Shear stress inhibits smooth muscle cell migration via nitric oxide-mediated downregulation of matrix metalloproteinase-2 activity

Garanich¹,

Pahakis²,

Tarbell³

2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…In a high blood flow model of intimal atrophy in polytetrafluoroethylene (PTFE) aortoiliac grafts, extracts of 4-day high-flow intimas degraded more vascular versican than similar extracts from 4-day low-flow intimas. 26 This activity was shown to be due to elevated plasmin levels. Versican is present throughout advanced lesions of atherosclerosis as well.…”

Section: Accumulation and Role In Lipid Retentionmentioning

confidence: 99%

Proteoglycans in Atherosclerosis and Restenosis

Wight

Merrilees

2004

Circulation Research

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334

243

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Abstract-The proteoglycan versican is one of several extracellular matrix (ECM) molecules that accumulate in lesions of atherosclerosis and restenosis. Its unique structural features create a highly interactive molecule that binds growth factors, enzymes, lipoproteins, and a variety of other ECM components to influence fundamental events involved in vascular disease. Versican is one of the principal genes that is upregulated after vascular injury and is a prominent component in stented and nonstented restenotic lesions. The synthesis of versican is highly regulated by specific growth factors and cytokines and the principal source of versican is the smooth muscle cell. Versican interacts with hyaluronan, a long chain glycosaminoglycan, to create expanded viscoelastic pericellular matrices that are required for arterial smooth muscle cell (ASMC) proliferation and migration. Versican is also prominent in advanced lesions of atherosclerosis, at the borders of lipid-filled necrotic cores as well as at the plaque-thrombus interface, suggesting roles in lipid accumulation, inflammation, and thrombosis. Versican influences the assembly of ECM and controls elastic fiber fibrillogenesis, which is of fundamental importance in ECM remodeling during vascular disease. Collectively, these studies highlight the critical importance of this specific ECM component in atherosclerosis and restenosis. Key Words: proteoglycans Ⅲ versican Ⅲ extracellular matrix Ⅲ atherosclerosis Ⅲ smooth muscle cells V ersican is a chondroitin sulfate proteoglycan (CSPG) that is present in the extracellular matrix (ECM) of normal blood vessels and increases dramatically in all forms of vascular disease. 1,2 A number of reports within the last few years have documented a significant involvement of versican in lesions of atherosclerosis and restenosis and these observations, coupled to those that demonstrate that this ECM proteoglycan regulates many of the events that contribute to the formation of atherosclerotic and restenotic lesions, highlights the critical importance of versican in the pathogenesis of vascular disease.Versican is one of many proteoglycans identified in vascular tissue or synthesized by vascular cells 3 and together with biglycan, decorin, and perlecan constitute the bulk of the proteoglycans found in the interstitial space. 2 Versican interacts with hyaluronan, a long chain high molecular weight glycosaminoglycan (GAG), that is also present in the extracellular matrix (ECM) of blood vessels and increases as versican in vascular disease. 4 The versican gene and protein follow a domain template. The amino-terminal globular domain (G1) binds hyaluronan, and the carboxy-terminal globular domain (G3) resembles the selectin family of proteins, consisting of a C-type lectin adjacent to two epidermal growth factor (EGF) domains and a complement regulatory region. The middle region of the versican core protein is encoded by two large exons that specify the chondroitin sulfate attachment regions of versican (Figure 1). These highly interactiv...

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Increased Plasmin and Serine Proteinase Activity During Flow-Induced Intimal Atrophy in Baboon PTFE Grafts

Cited by 55 publications

References 46 publications

Accumulation and Loss of Extracellular Matrix During Shear Stress-mediated Intimal Growth and Regression in Baboon Vascular Grafts

Accumulation and Loss of Extracellular Matrix During Shear Stress-mediated Intimal Growth and Regression in Baboon Vascular Grafts

Shear stress inhibits smooth muscle cell migration via nitric oxide-mediated downregulation of matrix metalloproteinase-2 activity

Proteoglycans in Atherosclerosis and Restenosis

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