Local effects of nitric oxide supplementation and suppression in the development of intimal hyperplasia in experimental vein grafts

Fulton, Gregory J.; Barber, Lizzie; Gray, John; Svendsen, Einar; Hagen, Per Otto

doi:10.1016/s1078-5884(98)80030-0

Cited by 32 publications

(23 citation statements)

References 33 publications

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“…Previous studies have augmented NO levels, however, these alternative means of NO supplementation have not made it to the clinical arena due to several limitations. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]35] Systemic administration of NO is rapidly inactivated by hemoglobin in the circulating blood resulting in limited bioavailability. To overcome this limitation, larger doses of the NO donor must be administered systemically; however, these larger doses can produce adverse systemic hemodynamic and hemostatic effects, thereby precluding administration of biologically effective doses of NO.…”

Section: Discussionmentioning

confidence: 99%

“…This has been demonstrated in numerous animal models which have utilized varying NO delivery methods including inhalational NO, delivery of the substrate L-arginine, delivery of NO-donors systemically or locally, gene therapy with endothelial NO synthase (eNOS) or inducible NO synthase (iNOS), and polymer-based approaches of NO-donor delivery. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] All of these therapies have demonstrated varying degrees of success, yet none have been used in the clinical arena due to significant side effects, safety concerns, complexity of administration and, sometimes, lack of significant and durable effect.…”

Section: Introductionmentioning

confidence: 99%

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Beneficial effect of a short-acting NO donor for the prevention of neointimal hyperplasia

Pearce

Najjar

Kapadia

et al. 2008

Free Radical Biology and Medicine

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Nitric oxide (NO)-based therapies effectively inhibit neointimal hyperplasia in animal models of arterial injury and bypass grafting, but are not available clinically. We created a simple, effective, locally-applied NO-eluting therapy to prevent restenosis following vascular procedures. We investigated the efficacy of perivascular delivery of two different distinctly different diazeniumdiolate NO donors, 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/ NO), (short half-life) and diazeniumdiolated poly(acrylonitrile) (PAN/NO), (long half-life), in powder or gel form (30% poloxamer 407), at inhibiting neointimal hyperplasia using the rat carotid artery injury model. Two weeks post-injury, all of the NO-eluting therapies successfully reduced neointimal hyperplasia. However, most dramatically, PROLI/NO powder reduced intimal area by 91.2% (P<0.05) versus injury alone. PROLI/NO powder was noted to reduce the medial area (40.2% vs. injury alone, P<0.05), while other groups showed no such effect. Three days post-injury, each NO treatment group significantly reduced cellular proliferation. However, inflammatory markers revealed a distinct pattern: PAN/NO groups displayed increased leukocyte infiltration (P<0.05) whereas PROLI/NO groups displayed less macrophage infiltration (P<0.05). In conclusion, perivascular delivery of diazeniumdiolate NO donors in powder or gel form effectively inhibits neointimal hyperplasia. Application of short-acting PROLI/NO powder most effectively inhibited neointimal hyperplasia and inflammation and may represent a simple, clinically applicable NOeluting therapy to prevent neointimal hyperplasia and restenosis following open vascular interventions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Beneficial effect of a short-acting NO donor for the prevention of neointimal hyperplasia

Pearce

Najjar

Kapadia

et al. 2008

Free Radical Biology and Medicine

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“…The phenotypic modulation of SMCs associated with vein grafting has been shown to alter ECM synthesis characterized by increasing collagen type I and elastin production [130,131]. Veins used as arterial bypass grafts undergo an alteration of their ECM components [225], which can result in a loss of lumenal area and eventual occlusion [15,226]. An alteration in matrix synthesis directly leads to increased collagen content in the hyperplastic neointima during the first week after injury resulting from balloon angioplasty [227].…”

Section: Remodelingmentioning

confidence: 99%

In Situ Bioengineering of Arterial Vein Grafts

El-Kurdi

Morelli

Hong

et al. 2008

ASME 2008 Summer Bioengineering Conference, Parts a and B

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The autogenous saphenous vein remains the graft of choice for both coronary (500,000 annually in the US) and peripheral (80,000 annually) arterial bypass procedures. Failure of arterial vein grafts (AVGs) remains a major problem, and patients with failed grafts will die or require reoperation. Intimal hyperplasia (IH) accounts for 20% to 40% of all AVG failures. It is believed that this adverse pathological response by AVGs is largely due to their abrupt exposure to the significantly elevated circumferential wall stress (CWS) associated with the arterial system. We believe that if an AVG is given an ample opportunity to adapt and remodel to the stresses of its new environment, cellular injury may be reduced, thus limiting the initiating mechanisms of IH.The goal of this work was to develop a new mechanical conditioning paradigm, in the form of a peri-adventitially placed, biodegradable polymer wrap, to safely and functionally "arterialize" AVGs in situ. The polymer wrap was tuned so that as it degraded over a desired period of time, the mechanical support offered by it was reduced and the vein was exposed to gradually increasing levels of CWS in situ.To investigate the effects of mechanical conditioning on AVGs, we utilized both our well established, validated ex vivo vascular perfusion system (EVPS) as well as an appropriate preclinical animal model. The "engineering" component of this bioengineering study was to enhance our EVPS capabilities. Enhancements were made in the form of rigorous mathematical modeling, via subspace system identification, and automatic feedback control, via proportional iv integral and derivative control, of the arterial CWS and shear stress waveform generation capabilities of the EVPS. Pairs of freshly harvested porcine internal jugular veins (PIJVs) were perfused ex vivo under several biomechanical conditions. The acute hyperplastic response of PIJVs abruptly exposed to arterial hemodynamic conditions was compared to PIJVs perfused under normal venous conditions. In an attempt to attenuate this acute hyperplastic response, an ex vivo mechanical conditioning paradigm was imposed onto the PIJVs both via manual adjustment of EVPS parameters and via an adventitially placed tuned electrospun biodegradable polymer wrap. Early markers of IH were evaluated post-perfusion, and they included vascular smooth muscle cell apoptosis, proliferation, and phenotypic modulation. Quantification of these markers via immunohistochemical techniques provided the foundation for the final stage of this work. To assess the efficacy of the tuned electrospun biodegradable polymer wrap in attenuating the development of intimal hyperplasia in AVGs, a series of preclinical studies was performed in a pig model. PIJVs abruptly exposed to arterial levels of CWS showed a significant increase in apoptosis and in the number of synthetic smooth muscle cells, as well as a decrease in proliferation. Mechanical conditioning, via both manual adjustment of the EVPS parameters and placement of the biodegradable adventitial wra...

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“…For vein grafts inserted into arterial circulation this factor is implicated as the genesis for postoperative recurrent occlusions 1 . In vasculopathies related to heart transplants, it has been proven that this phenomenon plays a decisive role 2 .…”

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confidence: 99%

Efeito da L-arginina na neoproliferação intimal e no remodelamento arterial após lesão por balão, em ilíacas de coelhos hipercolesterolêmicos

Knopfholz¹,

Précoma²,

Brofman³

et al. 2006

Arq. Bras. Cardiol.

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objective: It has been implied that neointimal proliferation and remodeling are the major causes of restenosis. The objective of this study is to assess the effect of orally administered L-arginine on these two factors in hypercholesterolemic rabbits that had suffered an injury to their iliac arteries caused by a catheter balloon. Methods:The study included nineteen rabbits that were divided in two groups: control (CG) and arginine (AG). There were 19 arteries studied from the control group and 17 in the arginine group. The animals were placed on a 2% hypercholesterolemic diet for 15 days and then submitted to a balloon angioplasty in order to produce a lesion in their iliac arteries. Next, the AG animals were given a 1g/kg/day oral dose of a L-arginine solution. The animals were sacrificed 15 days after the angioplasty procedure and histological artery sections were prepared, stained and fixed. The ratio between the neointimal area (in mm 2 ) and the media layer (in mm 2 ) was used to represent lesion development. In order to determine remodeling, the ratio between the total area of the medial portion of the vessel (greater balloon contact) and the total area of the reference segment of the vessel (less balloon contact) was used.results: Mean neointimal thickness (NI/M) was 0.8151±0.2201 in CG and 0.3296±0.1133 in AG. Remodeling patterns for the two groups studied were similar. conclusion: In the experimental model used, L-arginine was able to reduce intimal tissue thickness in hypercholesterolemic rabbits but did not act on artery remodeling.

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Local effects of nitric oxide supplementation and suppression in the development of intimal hyperplasia in experimental vein grafts

Abstract: These data confirm the protective effect of NO in vascular injury and suggest that NO synthase activity is either absent or reduced to such a level that further inhibition in this short time course is not relevant to the pathophysiology of vein graft intimal hyperplasia.

Cited by 32 publications

References 33 publications

Beneficial effect of a short-acting NO donor for the prevention of neointimal hyperplasia

Beneficial effect of a short-acting NO donor for the prevention of neointimal hyperplasia

In Situ Bioengineering of Arterial Vein Grafts

Efeito da L-arginina na neoproliferação intimal e no remodelamento arterial após lesão por balão, em ilíacas de coelhos hipercolesterolêmicos

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