Nitric Oxide Modulates Basal and Endothelin-induced Coronary Artery Vascular Smooth Muscle Cell Proliferation and Collagen Levels

Rizvi, Masood Ahmad; Myers, Paul R.

doi:10.1006/jmcc.1996.0480

Cited by 72 publications

(52 citation statements)

References 36 publications

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“…Previous experiments have demonstrated that NO donors added directly to the VSMC growth medium decreased collagen I concentrations, but not collagen III concentrations. 21 Kolpakov et al 22 have also previously found that NO inhibits total protein and collagen synthesis in noncoronary VSMCs.…”

Section: Discussionmentioning

confidence: 92%

“…Although the identity of the exact factor(s) is unknown, this observation is in agreement with previously published data on the antimitogenic effects of NO. 21 In summary, endogenously derived endothelial cell products, via a paracrine mechanism, can alter extracellular matrix metabolism. The coronary artery endothelium cocultured with coronary VSMCs resulted in a time-dependent increase in the concentration of collagen type I, but not collagen type III; instead, collagen type III decreased.…”

Section: Discussionmentioning

confidence: 99%

“…The vasomotor actions of NO are well characterized (for review, see Reference 1). Nitric oxide also is a potent inhibitor of platelet aggregation, 2,3 an antimitogen, [4][5][6][7] an inhibitor of cell migration, 8 and an immunomodulator. 9 -11 Alterations and/or abnormalities in NO metabolism have been implicated in a variety of diseases, especially atherosclerosis [12][13][14][15] and, more recently, restenosis.…”

mentioning

confidence: 99%

“…Prior research has demonstrated that NO donors alter collagen metabolism when added directly to VSMCs 21,22 ; however, less is known with regard to the role of endogenously derived NO in vascular wall extracellular matrix metabolism. Since previous work has established that NO is produced by an endothelial constitutive enzyme, the experimental design employed a NOS antagonist to block endogenous synthesis of NO.…”

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confidence: 99%

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Vascular Endothelial Cell Regulation of Extracellular Matrix Collagen

Myers

Tanner

1998

ATVB

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Abstract-Endothelium-derived products have been implicated in the regulation of vascular wall structure through their effects on extracellular matrix metabolism. The purpose of this study was to further understand the paracrine mechanisms underlying endothelial cell regulation of extracellular matrix metabolism by testing the hypothesis that endothelium-derived nitric oxide decreases the concentration of soluble collagens derived from vascular smooth muscle cells (VSMCs). Porcine coronary endothelium and VSMCs were grown under a coculture configuration to assess the paracrine effects of nitric oxide produced by the endothelium on VSMC collagen types I and III. Endogenous endothelial cell nitric oxide production was blocked with N -nitro-L-arginine methyl ester. Collagen type I and type III were quantitatively measured using an enzyme-linked immunosorbent assay method. The endothelium elicited a timedependent increase in the concentration of soluble VSMC-derived collagen type I; in contrast, collagen type III was decreased. After inhibition of nitric oxide production, there was a marked increase in both collagen types I and III concentration. These results demonstrated that endothelium-derived nitric oxide differentially alters collagen subtypes produced by VSMCs. The data support the hypothesis that nitric oxide functions via a paracrine mechanism to decrease VSMC collagen types I and III concentration, a finding consistent with an integral role for the endothelium in modulating extracellular matrix metabolism. (Arterioscler Thromb Vasc Biol. 1998;18:717-722.) Key Words: extracellular matrix Ⅲ nitric oxide Ⅲ collagen Ⅲ endothelium N itric oxide is an endothelium-derived compound that exerts multiple effects on the vasculature through its paracrine actions on the vessel wall, as well as on formed blood elements. The vasomotor actions of NO are well characterized (for review, see Reference 1). Nitric oxide also is a potent inhibitor of platelet aggregation, 2,3 an antimitogen, 4-7 an inhibitor of cell migration, 8 and an immunomodulator.9 -11 Alterations and/or abnormalities in NO metabolism have been implicated in a variety of diseases, especially atherosclerosis 12-15 and, more recently, restenosis. 16,17 The multiple actions of NO and its role in vascular wall disease are consistent with an important role in the metabolism of the extracellular matrix.The vascular wall extracellular matrix comprises the bulk of the interstitium of the media and is composed of a complex mixture of extracellular matrix proteins, including collagens. 18 The fibrillar collagens are the most abundant collagens, with subtypes I, III, and IV being most common. 18,19 Atherogenesis and restenosis are two disease processes relevant to coronary artery vascular biology that are directly related to extracellular matrix collagen synthesis and degradation, primarily because the hallmark of the disease is mechanical obstruction of coronary blood flow secondary to medial and intimal hyperplasia. The importance of a functionally intact endotheliu...

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Vascular Endothelial Cell Regulation of Extracellular Matrix Collagen

Myers

Tanner

1998

ATVB

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“…iNOS was chosen as a model therapeutic gene for these studies because of its previous efficacious use in delivery-catheter genetherapy studies with a pig coronary stent angioplasty model (24) and the fact that iNOS can inhibit SMC proliferation (32,33) and migration (34), platelet activation (35), and extracellular-matrix production (32). Thus, the therapeutic potential of iNOS is far broader than any of the current pharmaceuticals used with drugeluting stents.…”

Section: Discussionmentioning

confidence: 99%

Bisphosphonate-mediated gene vector delivery from the metal surfaces of stents

Fishbein

Alferiev

Nyanguile

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

130

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The clinical use of metallic expandable intravascular stents has resulted in improved therapeutic outcomes for coronary artery disease. However, arterial reobstruction after stenting, in-stent restenosis, remains an important problem. Gene therapy to treat in-stent restenosis by using gene vector delivery from the metallic stent surfaces has never been demonstrated. The present studies investigated the hypothesis that metal-bisphosphonate binding can enable site-specific gene vector delivery from metal surfaces. Polyallylamine bisphosphonate (PAA-BP) was synthesized by using Michael addition methodology. Exposure to aqueous solutions of PAA-BP resulted in the formation of a monomolecular bisphosphonate layer on metal alloy surfaces (steel, nitinol, and cobaltchromium), as demonstrated by x-ray photoelectron spectroscopy. Surface-bound PAA-BP enabled adenoviral (Ad) tethering due to covalent thiol-binding of either anti-Ad antibody or a recombinant Ad-receptor protein, D1. In arterial smooth muscle cell cultures, alloy samples configured with surface-tethered Ad were demonstrated to achieve site-specific transduction with a reporter gene, (GFP). Rat carotid stent angioplasties using metal stents exposed to aqueous PAA-BP and derivatized with anti-knob antibody or D1 resulted in extensive localized Ad-GFP expression in the arterial wall. In a separate study with a model therapeutic vector, Adinducible nitric oxide synthase (iNOS) attached to the bisphosphonate-treated metal stent surface via D1, significant inhibition of restenosis was demonstrated (neointimal͞media ratio 1.68 ؎ 0.27 and 3.4 ؎ 0.35; Ad-iNOS vs. control, P < 0.01). It is concluded that effective gene vector delivery from metallic stent surfaces can be achieved by using this approach.gene therapy ͉ local delivery ͉ restenosis T he use of balloon expandable metallic stents has resulted in improved therapeutic outcomes for coronary artery disease (1). However, stent angioplasty is complicated in many patients by reobstruction due to the formation of a neointima in the stented arterial segment, a disease process known as in-stent restenosis (2). The mechanisms responsible for instent restenosis involve proliferation and migration of medial smooth muscle cells (SMCs) and an associated increase in extracellular matrix components (2). The use of polymercoated drug-eluting stents has markedly decreased the incidence of in-stent restenosis observed with unmodified metal stents (3). However, both experimental (4) and clinical (5) studies indicate a number of concerns about this approach, because polymer coatings on stents cause a more pronounced inf lammatory response than metal surfaces (6), thus delaying rather than preventing restenosis (7,8).Polymer-coated gene-delivery stents have been demonstrated in animal studies to be effective for both reporter (9-13) and therapeutic (14, 15) vector delivery. Nevertheless, their use is problematic because of harmful properties of the polymer coatings (6, 7). Therefore, the present experiments investigated gene deli...

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Homocyst(e)ine induces calcium second messenger in vascular smooth muscle cells

2000

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Homocysteine found in the plasma of patients with coronary heart disease, induces vascular smooth muscle cell (VSMC) proliferation and increases deposition of extracellular matrix (ECM) components. Yet, the mechanism by which homocysteine mediates this effect and its role in vascular disease is largely unknown. We hypothesized that homocysteine induces ECM production via intracellular calcium release in VSMC. To test this hypothesis, aortic VSMC from Sprague-Dawley rats were isolated and characterized by positive labeling for vascular smooth muscle alpha-actin. Early passage cells (p2-3) were grown in monolayer on coverslips. Calcium transients were quantified with fura2/AM spectrofluorometry. Homocysteine induced intracellular calcium [Ca(2+)](i) transients with an EC(50) of 60 +/- 5 nM. The EC(50) for glutathione and cysteine were 10 and 100-fold lower, respectively. Depleting extracellular calcium did not alter the homocysteine effect on intracellular calcium; however, thapsigargin pretreatment, which depletes intracellular Ca(2+) stores, abolished the homocysteine effect, demonstrating its dependence on intracellular Ca(2+) stores. Extracellular sodium depletion significantly (P < 0.05) increased [Ca(2+)](i) also suggesting a possible role of sodium-calcium exchange in the process. To begin to elucidate the intracellular pathways by which homocysteine might act, VSMC were pretreated with specific inhibitors and stimulators prior to homocysteine stimulation. Staurosporine and phorbol myrisate acetate (PMA), potent simulators of protein kinase C, augmented the release of Ca(2+) by homocysteine. Interestingly, pretreatment with the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) greatly exacerbated the sensitivity of VSMC to homocysteine. In contrast, pretreatment with either the phospholipase A(2) activator neomycin, the antioxidant and hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitor, pravastatin, the tyrosine kinase inhibitor genestein, or the calcium channel blocker, felodipine completely inhibited the homocysteine-induced Ca(2+) signal in VSMC. This suggests the role of multiple signaling pathways in the homocysteine effect on VSMC Ca(2+). Effects of homocysteine on collagen production, as ascertained by immunoblot analysis, correlated with its effect in intracellular calcium. Regardless of the signaling pathways involved, homocysteine, by virtue of its role on VSMC proliferation and ECM deposition, has the potential to affect vascular reactivity. To determine the effect of homocysteine on the ability of VSMC to react to potent agonist such as angiotensin II, VSMC were pretreated with homocysteine and exposed to a range of angiotensin II concentrations which normally have no effect on intracellular Ca(2+). After homocysteine pretreatment, VSMC were extremely responsive to angiotensin II at concentrations well below the physiologic range. These data taken together suggested that an initial effect of homocysteine is to induce release of intracellular Ca(2+) in V...

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Nitric Oxide Modulates Basal and Endothelin-induced Coronary Artery Vascular Smooth Muscle Cell Proliferation and Collagen Levels

Cited by 72 publications

References 36 publications

Vascular Endothelial Cell Regulation of Extracellular Matrix Collagen

Vascular Endothelial Cell Regulation of Extracellular Matrix Collagen

Bisphosphonate-mediated gene vector delivery from the metal surfaces of stents

Homocyst(e)ine induces calcium second messenger in vascular smooth muscle cells

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