Contribution of Adventitial Myofibroblasts to Vascular Remodeling and Lesion Formation after Experimental Angioplasty in Pig Coronary Arteries<sup>a</sup>

Wilcox, Josiah N.; Cipolla, Gustavo D.; Martin, Francis H.; Simonet, Lizette; Dunn, Bradley; Ross, Cheryl E.; Scott, Neal A.

doi:10.1111/j.1749-6632.1997.tb52025.x

Cited by 40 publications

(22 citation statements)

References 57 publications

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“…The cellular types within the adventitia (mainly fibroblasts and myofibroblasts) are known to be more susceptible to adenoviral transduction than medial SMC (28), perhaps explaining the high extent of transduction in the adventitia observed in our reporter studies (Table 2). Considering the active role the adventitia plays in the formation of neointimal lesions (29), the ability of the stent-delivery approach investigated herein to transduce cells in the adventitia might be therapeutically relevant. Importantly, the penetration of the vector into the adventitia did not result in the dissemination of the virus beyond the stented arterial segment, as verified by the GFP-PCR results.…”

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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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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“…Protein/DNA ratios in day-4 injured vehicle-treated vessels were unchanged ( Figure 2B), suggesting, together with Figure 2A data, that cell number declined in IM and adventitia at day 4, due to either cell necrosis and/or apoptosis 15 offsetting the proliferation known to be present in both layers at this time 1,2,15 or from possible migration of AFBs to the IM. 2,3 Thus, medial and adventitial thickening at day 4 ( Figure 1) presumably reflects edema and/or increased extracellular matrix and not increased cell number. In day-12 vessels, protein content in IM returned to control, but DNA increased 37% (Figure 2A).…”

Section: Baseline Dna and Protein Content In Normal And Balloon-injurmentioning

confidence: 99%

“…These baseline data are consistent with the time-course of proliferation and centripetal migration of SMCs and AFBs reported in balloon-injured rat and porcine arteries. [1][2][3]15 …”

Section: Baseline Dna and Protein Content In Normal And Balloon-injurmentioning

confidence: 99%

“…1 Recent evidence has shown that adventitial fibroblasts (AFBs) can also contribute (by as much as 50%) to neointimal lesion growth. 2,3 Wilcox et al 2 found that AFB proliferation began within hours after balloon injury and exceeded medial SMC proliferation measured over 4 weeks. Moreover, AFBs modulated to myofibroblasts, ie, ␣-smooth muscle actin (␣SM-actin) expressing cells, by one week after injury, followed by deposition of a collagen-rich adventitial thickening.…”

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confidence: 99%

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Trophic Effect of Norepinephrine on Arterial Intima-Media and Adventitia Is Augmented by Injury and Mediated by Different α1-Adrenoceptor Subtypes

Zhang

Faber

2001

Circulation Research

102

156

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Abstract-In vivo studies have suggested that norepinephrine (NE) directly contributes to normal vascular wall growth and worsening of hypertrophy, atherosclerosis, and restenosis. However, it is unknown whether these effects are secondary to hemodynamic changes caused by systemic NE or ␣-adrenoceptor (AR) antagonists. Herein, we determined if NE directly stimulates growth of medial smooth muscle cells (SMCs) and adventitial fibroblasts (AFBs) that we have shown express ␣1-ARs in similar abundance. The rat aorta was isolated before injury, 4 days after, or 12 days after balloon injury, and maintained under circumferential tension in organ culture for 48 hours with 1 mol/L NE. Intima-media and adventitia were separated and DNA content, protein synthesis, and protein content measured. In uninjured aorta, NE increased DNA and protein content similarly in adventitia, and increased only protein content in intima-media, suggesting AFB proliferation and SMC hypertrophy. In vessels isolated 4 or 12 days after injury, NE increased all 3 endpoints in both layers by up to 20-fold greater than in uninjured vessels. These effects were dose-dependent and were unaffected by ␣2-or ␤-AR blockade (except increased DNA content in adventitia that was also inhibited by ␣2-AR blockade). Intima-media growth was blocked by KMD3213 (␣1A-AR antagonist) and adventitial growth by AH11110A (␣1B-AR antagonist), whereas BMY7378 (␣1D-AR antagonist) had no effect. NE decreased SMC marker proteins (eg, ␣-smooth muscle actin and desmin) and augmented the changes induced by injury. These data suggest that prolonged stimulation of ␣1A-and ␣1B-ARs induces growth of SMCs and AFBs, respectively, that is significantly augmented by injury. Key Words: artery Ⅲ smooth muscle cell Ⅲ adventitial fibroblast Ⅲ growth Ⅲ organ culture E ndothelial injury, eg, by balloon angioplasty, causes smooth muscle cells (SMCs) to begin proliferating within two days and to migrate to the intima where they proliferate and form lumen-narrowing lesions. 1 Recent evidence has shown that adventitial fibroblasts (AFBs) can also contribute (by as much as 50%) to neointimal lesion growth. 2,3 Wilcox et al 2 found that AFB proliferation began within hours after balloon injury and exceeded medial SMC proliferation measured over 4 weeks. Moreover, AFBs modulated to myofibroblasts, ie, ␣-smooth muscle actin (␣SM-actin) expressing cells, by one week after injury, followed by deposition of a collagen-rich adventitial thickening. Similar findings have been reported by others. 3 Whether catecholamines directly influence vascular wall growth is unknown because of difficulty in distinguishing a direct action from trophic effects of altered arterial pressure and blood flow velocity that accompany changes in sympathetic activity or plasma catecholamines. Therefore, support for this hypothesis remains indirect: (1) most large arteries are innervated with adrenergic nerves 4 ; (2) medial SMCs of large arteries express multiple ␣-adrenoceptor (AR) subtypes, several of which do not mediate constri...

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“…Adventitial fibroblasts also participate in lesion formation by differentiating into myofibroblasts and migrating to the neointima. 82 As discussed above, ROS are able to induce these phenotypic changes, suggesting that they may contribute to the pathogenesis of restenosis in vivo.…”

Section: Restenosis After Angioplastymentioning

confidence: 99%

Molecular and Cellular Mechanisms

2010

Radiation Hormesis and the Linear-No-Threshold Assumption

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Abstract-Accumulating evidence indicates that reactive oxygen species (ROS) play major roles in the initiation and progression of cardiovascular dysfunction associated with diseases such as hyperlipidemia, diabetes mellitus, hypertension, ischemic heart disease, and chronic heart failure. ROS produced by migrating inflammatory cells as well as vascular cells (endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts) have distinct functional effects on each cell type. These include cell growth, apoptosis, migration, inflammatory gene expression, and matrix regulation. ROS, by regulating vascular cell function, can play a central role in normal vascular physiology, and can contribute substantially to the development of vascular disease. Key Words: antioxidants Ⅲ vascular disease Ⅲ muscle, smooth, vascular Ⅲ endothelium Ⅲ free radicals Ⅲ macrophages Ⅲ oxidative stress A ccumulating evidence indicates that oxidative stress plays a major role in the initiation and progression of cardiovascular dysfunction associated with diseases such as hyperlipidemia, diabetes mellitus, hypertension, ischemic heart disease, and chronic heart failure. Oxidative stress is a state in which excess reactive oxygen species (ROS) overwhelm endogenous antioxidant systems. ROS have distinct functional effects on each cell type in the vasculature and can play both physiological and pathophysiological roles. In this review, we will focus on vascular endothelial cells (ECs) and smooth muscle cells (VSMCs), because the effects of ROS on adventitial fibroblasts were reviewed recently. 1 We will also briefly discuss the clinical implications of oxidative stress. Reactive Oxygen Species Enzymatic Superoxide ProductionMultiple enzymatic systems produce O 2 ·Ϫ and its derivatives in the vasculature, including NAD(P)H oxidases, XO, nitric oxide synthases (NOS), and MPO. The relative importance of each of these proteins appears to vary with the physiological state of the vasculature. NAD(P)H oxidases consist of multiple subunits: the electron transfer moieties (gp91phox, nox1 or nox4), p22phox, and regulatory subunits (p47phox, p67phox, and rac1). The expression pattern of these subunits varies among vascular cells. 4 What makes the NAD(P)H oxidases so important in vascular function is their responsiveness to a variety of agonists, such as angiotensin (Ang) II. 5 Enzyme activation occurs over the short term by stimulation of specific intracellular signals 6 and over the long term by upregulation of the enzyme subunits. 7,8 Even low Ang II concentrations (0.1 nmol/L) increase NAD(P)H oxidase-derived ROS, suggesting that this enzyme system is important physiologically. 5 In ROS have been implicated in various clinicopathologic entities, including ischemia/reperfusion injury, hypercholesterolemia and endothelial dysfunction in chronic heart failure. 11,12 Recently, the role of MPO in vascular pathology has been highlighted. MPO is abundant in phagocytes and catalyzes H 2 O 2 to produce HOCl and other oxidizing species. 13 It also uti...

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Contribution of Adventitial Myofibroblasts to Vascular Remodeling and Lesion Formation after Experimental Angioplasty in Pig Coronary Arteries^a

Cited by 40 publications

References 57 publications

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

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

Trophic Effect of Norepinephrine on Arterial Intima-Media and Adventitia Is Augmented by Injury and Mediated by Different α1-Adrenoceptor Subtypes

Molecular and Cellular Mechanisms

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Contribution of Adventitial Myofibroblasts to Vascular Remodeling and Lesion Formation after Experimental Angioplasty in Pig Coronary Arteriesa

Cited by 40 publications

References 57 publications

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

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

Trophic Effect of Norepinephrine on Arterial Intima-Media and Adventitia Is Augmented by Injury and Mediated by Different α1-Adrenoceptor Subtypes

Molecular and Cellular Mechanisms

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Contribution of Adventitial Myofibroblasts to Vascular Remodeling and Lesion Formation after Experimental Angioplasty in Pig Coronary Arteries^a