Nitric Oxide Synthase and Adenylyl and Guanylyl Cyclase Activity in Porcine Interposition Vein Grafts

Jeremy, Jamie Y.; Dashwood, Michael R.; Timm, Maureen; Izzat, Frcs Mohammad Bashar; Mehta, Frcs Dheeraj; Bryan, Frcs Alan J; Angelini, Frcs Gianni D

doi:10.1016/s0003-4975(96)01144-7

Cited by 41 publications

(23 citation statements)

References 22 publications

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“…11,35,36 The ability of cells to synthesize cAMP and cGMP is high in healthy uninjured vessels, 37 and this probably contributes toward the maintenance of VSMC quiescence. Furthermore, reduced synthesis of cyclic nucleotides after vessel injury 37 is likely to be an important mechanism in removing the "brake" on proliferation.…”

Section: Discussionmentioning

confidence: 99%

Altered S-Phase Kinase-Associated Protein-2 Levels Are a Major Mediator of Cyclic Nucleotide–Induced Inhibition of Vascular Smooth Muscle Cell Proliferation

Bond

Sala-Newby

et al. 2006

Circulation Research

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Abstract-Cyclic nucleotides inhibit vascular smooth muscle cell (VSMC) proliferation but the underlying molecular mechanisms are incompletely understood. We studied the role of S-phase kinase-associated protein-2 (Skp2), an F-box protein of SCF Skp2 ubiquitin ligase responsible for polyubiquitylation of and subsequent proteolysis of p27 Kip1 , a key step leading to cell cycle progression. Skp2 mRNA and protein were upregulated in mitogen-stimulated VSMCs and after balloon injury in rat carotid arteries, where the time course and location of Skp2 expression closely paralleled that of proliferating cell nuclear antigen. Skp2 small interference RNA (siRNA) reduced Skp2 expression, increased p27 Kip1 levels, and inhibited VSMC proliferation in vitro. cAMP-elevating agents prominently inhibited VSMC proliferation and Skp2 expression through inhibiting Skp2 transcription as well as decreasing Skp2 protein stability. Consistent with this, activation of protein kinase A, a downstream target of cAMP, was shown to negatively regulate focal adhesion kinase (FAK) phosphorylation and Skp2 expression. Adenovirus-mediated Skp2 expression reversed cAMP-induced p27Kip1 upregulation and rescued cAMP-related S-phase entry inhibition up to 50%. 8-Bromo-cGMP also moderately reduced Skp2 and cell proliferation when VSMCs were incubated with low serum concentration. Interestingly, we showed that 8-bromo-cGMP inhibited Skp2 expression also through activation of protein kinase A, not protein kinase G, which conversely enhanced FAK Y397 phosphorylation and Skp2 expression. After balloon injury of rat carotid arteries, local forskolin treatment significantly reduced FAK Y397 phosphorylation, Skp2 expression, VSMC proliferation, and subsequent neointimal thickening. These data demonstrate for the first time that Skp2 is an important factor in VSMC proliferation and its inhibition by cyclic nucleotides. Key Words: Skp2 Ⅲ cyclic nucleotides Ⅲ smooth muscle cell Ⅲ proliferation Ⅲ focal adhesion kinase V ascular smooth muscle cell (VSMC) proliferation contributes to intima formation after balloon injury with and without stenting, venous graft failure, transplant vasculopathy, and atherosclerosis. This motivates efforts to understand the regulation of VSMC proliferation and in particular to identify pathways that could mediate inhibition of proliferation. In healthy, uninjured vessels, VSMCs are quiescent and exhibit extremely low rates of proliferation, even in the presence of mitogenic stimuli. 1 The mechanisms responsible for overcoming VSMC quiescence and initiating VSMC proliferation in response to vessel injury include release of growth factors 2,3 and remodeling of the vascular extracellular matrix. 4 -6 This stimulates signaling pathways downstream of growth factor receptors or focal adhesions, respectively. [7][8][9] Signaling pathways related to cell-cell adhesion through cadherins may also be involved. 10 Cell-type specific antiproliferative effects of cyclic nucleotides (cAMP and cGMP) are well documented. 11 In particular, incre...

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Section: Discussionmentioning

confidence: 99%

Altered S-Phase Kinase-Associated Protein-2 Levels Are a Major Mediator of Cyclic Nucleotide–Induced Inhibition of Vascular Smooth Muscle Cell Proliferation

Bond

Sala-Newby

et al. 2006

Circulation Research

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“…12 The right jugular vein was cannulated with a 24-gauge catheter. A 2F Fogarty balloon catheter was inserted, and after the balloon was inflated with 0.2 mL of air, the intima of the jugular vein was denuded by three passages of the catheter.…”

Section: Animal Preparationmentioning

confidence: 99%

Accelerated Reendothelialization With Suppressed Thrombogenic Property and Neointimal Hyperplasia of Rabbit Jugular Vein Grafts by Adenovirus-Mediated Gene Transfer of C-Type Natriuretic Peptide

et al. 2002

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“…In brief, PIJVs were harvested according to Section 3.1.1 and were either spun with the a same wrap composition and thickness as in Specific Aim 3 using the electrospinning process described in Section 3.1.2, or designated as sham controls. The AVGs were then implanted as carotid interposition grafts (as described in Section 4.1.1) for 30 days (or upon observing irreversible complications), an implant duration sufficient to allow IH to be grossly apparent in the sham control group [27,43,48,49,51,241,[294][295][296] to which the spun group was compared. In addition to evaluating patency via angiography, the explanted AVGs were processed for histological evaluation of IH, and for SEM as described in Section 3.2.6.…”

Section: Methodsmentioning

confidence: 99%

“…The porcine internal jugular vein (PIJV) was chosen as a model because of its similarity in inner diameter and wall thickness to the human greater saphenous vein, and because this tissue has previously been used to investigate the pathologic response of veins exposed to arterial hemodynamic conditions [43,49,51,81,163,221,248,273,[294][295][296]. The surgical harvest procedure was performed in the manner of a saphenectomy for bypass.…”

Section: Tissue Harvest and Transportmentioning

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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Nitric Oxide Synthase and Adenylyl and Guanylyl Cyclase Activity in Porcine Interposition Vein Grafts

Cited by 41 publications

References 22 publications

Altered S-Phase Kinase-Associated Protein-2 Levels Are a Major Mediator of Cyclic Nucleotide–Induced Inhibition of Vascular Smooth Muscle Cell Proliferation

Altered S-Phase Kinase-Associated Protein-2 Levels Are a Major Mediator of Cyclic Nucleotide–Induced Inhibition of Vascular Smooth Muscle Cell Proliferation

Accelerated Reendothelialization With Suppressed Thrombogenic Property and Neointimal Hyperplasia of Rabbit Jugular Vein Grafts by Adenovirus-Mediated Gene Transfer of C-Type Natriuretic Peptide

In Situ Bioengineering of Arterial Vein Grafts

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