Ann Thorac Surg 2005;80:939-944
© 2005 The Society of Thoracic Surgeons
Original article: Cardiovascular
Effect of Vein Graft Harvesting on Endothelial Nitric Oxide Synthase and Nitric Oxide Production
Michael R. Dashwood, PhD
a
,
*
,
Kay Savage, PhD
a
,
Audrey Dooley, PhD
b
,
Xu Shi-Wen, PhD
c
,
David J. Abraham, PhD
c
,
Domingos S.R. Souza, MD, PhD
d
a Department of Clinical Biochemistry, Royal Free and University College Medical School, Royal Free Campus, Pond Street, London, United Kingdom
b Department of Biochemistry, Royal Free and University College Medical School, Royal Free Campus, Pond Street, London, United Kingdom
c Department of Rheumatology, Royal Free and University College Medical School, Royal Free Campus, Pond Street, London, United Kingdom
d Department of Thoracic and Cardiothoracic Sugery, Örebro University Hospital, Örebro, Sweden
Accepted for publication March 8, 2005.
* Address reprint requests to Dr Dashwood, Clinical Biochemistry, Royal Free and University College Medical School, Royal Free Campus, Pond St, London NW3 2QG, United Kingdom (Email: mdashwood{at}rfc.ucl.ac.uk).
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Abstract
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BACKGROUND: Although the saphenous vein is the most commonly used conduit for coronary artery bypass surgery occlusion rates are high, with more than 50% grafts failing within 10 years. Nitric oxide, a potent vasodilator, also inhibits platelet aggregation, thrombus formation and vascular smooth muscle cell proliferation, is implicated in various vascular pathologies, including graft failure.
METHODS: Saphenous veins were obtained from patients undergoing bypass surgery harvested by conventional methods and with minimal handling, using a "no-touch" technique. Tissue distribution and protein expression of endothelial nitric oxide synthase was compared using immunohistochemistry and Western blot analysis. Nitric oxide generation was assessed using the citrulline assay.
RESULTS: There was injury to conventional compared with no-touch vein segments, in particular to the lumenal endothelium and tunica adventitia. This injury was accompanied by an absence of endothelial nitric oxide synthase immunostaining at regions of endothelial denudation and damaged adventitial layer of conventional veins and a significant reduction (p < 0.05) in endothelial nitric oxide synthase protein expression. Furthermore, nitric oxide release from conventional tissue extracts was significantly (p < 0.05) lower than no-touch vein segments.
CONCLUSIONS: Our results show that there is a reduction in endothelial nitric oxide synthase and nitric oxide release in saphenous veins harvested by conventional surgical methods compared with those prepared atraumatically. These observations may influence graft performance.
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Introduction
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Autologous saphenous vein is the most commonly used conduit for coronary artery bypass surgery (CABG), yet occlusion rates are high, with 15% to 30% occluding in the first year and more than 50% failing in 10 years [1]. During conventional preparation, this vessel suffers considerable structural damage, in particular to the endothelium and the tunica adventitia. An alternative "no-touch" technique of vein harvesting has been described, where the vein is dissected with minimal handling and retains its cuff of surrounding tissue [2]. In addition to preserving a normal architecture, veins harvested by the no-touch technique do not go into spasm and are not subjected to high-pressure distension, resulting in minimal damage to the endothelium [3]. A recent follow-up study describes a decreased rate of early graft failure in patients receiving no-touch vein grafts when compared with conventional grafts [4].
Nitric oxide (NO), a potent endothelium-dependent vasorelaxant synthesized from L-arginine by endothelial nitric oxide synthase (eNOS), plays an important role in maintaining vascular tone. Other properties beneficial to vein graft patency include the ability of NO to inhibit platelet aggregation, thrombus formation, leukocyte adhesion, and vascular smooth muscle cell proliferation [5]. In conventional CABG, a high proportion of veins go into spasm during harvesting, and this is overcome using vasodilators [6] or high-pressure saline distension, leading to endothelial damage [7] and impaired NO release. In addition, reduced NO release has been reported in human saphenous vein grafts [8] and experimental models of vein grafting [9]. By preparing the saphenous vein atraumatically, using the no-touch technique, endothelial integrity is maintained contributing to improved graft patency by preserving endothelium-derived NO [10]. Whereas early stages of graft failure are mainly due to thrombotic occlusion, later stages are associated with vascular smooth muscle cell (VSMC) proliferation, neointimal thickening, and reduced lumen size [11]. Clearly, reduced NO levels are involved in many features of graft failure. Recent evidence for a beneficial role of NO in maintained graft patency has been described where adenoviral eNOS transfection inhibits migration and proliferation of VSMCs and platelet adhesion in human saphenous vein tissue [12]. Using immunohistochemistry and Western blot analysis, we have shown that levels of eNOS are reduced in conventional vein grafts compared with veins harvested with minimal damage and that this is accompanied by a reduction in the veins’ ability to release NO.
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Material and Methods
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In this study, segments of saphenous vein used as bypass grafts, were harvested from a total of 19 patients (3 female, mean age 55.3 years [SD 15]; 16 male, mean age 67.7 years [SD 7.1]) undergoing CABG at Örebero University Hospital, Sweden. These studies conformed with the Declaration of Helsinki and were performed under local ethics committee approval and patients’ informed consent. All patients were hypertensive and New York Heart Association (NYHA) class III and were taking antihypertensive therapy, statins, and aspirin. Adjacent segments of saphenous vein from each patient were divided into a conventional and no-touch sample. Conventional veins were stripped of the cushion of surrounding tissue and routinely distended with saline at a pressure of 300 mm Hg (measured by manometry) for 1 minute, a pressure based on pilot studies into the pressure required to overcome vasospasm and similar to that described by other groups [13, 14]. The no-touch segments were prepared atraumatically, where the vein trunk was exposed and the vein removed complete with its cushion of surrounding perivascular tissue as described previously [3, 4]. These segments did not require distension as none went into spasm. Vein samples were collected and stored according to subsequent processing protocols.
For immunohistochemistry, samples of vein from all 19 patients were immediately placed onto solid CO2 and stored at –70°C until they were used for the localisation of endothelial cells and eNOS employing standard immunohistochemical techniques. Briefly, transverse sections were post-fixed in acetone, and labeling was performed with primary antibodies to identify endothelial cells (mouse anti-CD31; Dako Ltd, Glostrup, Denmark) and eNOS (rabbit anti-eNOS; Santa Cruz Biotechnology, Autogen Bioclear Ltd, Calne, United Kingdom). After a 1-hour incubation period, sections were rinsed and antibody staining was detected with a standard Avidin biotinylated complex/alkaline phosphatase method (Vector Labs, Burlingame, California). Double staining was also performed using immunofluorescence to check for dual expression of markers. After incubation with primary antibodies (CD31 and anti-eNOS), labeling was detected using Alexa 546 (red) labeled anti-mouse and 488 (green) labeled anti-rabbit secondary antibodies (Molecular Probes, Eugene, Oregon). After washing, sections were mounted with Vectashield (Vector Labs), visualized under epifluorescence and photographed.
Frozen samples were used for determination of eNOS and CD31 protein expression by Western blot analysis. Veins from 8 patients were frozen in liquid nitrogen as soon as possible (within 10 minutes) and stored at –70°C until use. Tissue was homogenized in ice-cold lysis buffer, protein concentration determined, protein extracts separated by sodium dodecyl suplhate–polyacrylamide gel electrophoresis, and blotted for eNOS and CD31. Filters were blocked overnight and proteins detected by a 1-hour incubation with rabbit anti-eNOS antibody (Santa Cruz) or mouse anti-CD31 antibody (Dako Labs), followed by incubation with biotinylated species-specific secondary antibodies for 1 hour. Resultant antigen-antibody complexes were detected by incubation with Avidin biotinylated complex reagent (Vector Labs) using the enhanced chemiluminescence substrate kit (Amersham Biosciences, Buckinghamshire, United Kingdom). After exposure, films were analyzed by scanning densitometry on an Ultroscan XL (LKB Wallac, Huntingdon, Cambridge, UK) and expression levels standardized using ß-actin.
The NO-producing capacity of vein segments was measured using the citrulline assay. Homogenates of vein segments from 8 patients were prepared as before and NOS activity determined by the conversion of [14C]-L-arginine to [14C]-L-citrulline using a NOS activity assay kit (Calbiochem, Nottingham, United Kingdom). After incubation of tissue lysate with reaction buffer (37°C for 1 hour), the reaction was stopped and radioactivity quantified in a liquid scintillation counter. The NOS activity was expressed in fmol·min–1
·mg–1 protein. Blanks were prepared by incubating in 1 mM of the competitive NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME), and rat cerebellum extract was used as a positive control.
Data Analysis
All values are expressed as mean ± SEM. A comparison was made between conventional and no-touch segments of the same veins, and the paired Student’s t test was performed using GraphPad Inplot software (GraphPad Software, San Diego, California). Statistical significance was inferred at p values less than 0.05.
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Results
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No-touch saphenous veins harvested with minimal surgical trauma retained an essentially normal architecture. The intima was thrown into folds, as these vessels had not been distended, and the endothelial cells (identified using CD31) of the lumen were intact. In contrast, conventional veins exhibited a dilated lumen, the intimal folds were absent and there were regions of endothelial denudation caused by high-pressure distension. Endothelial cells of the adventitial vasa vasorum of no-touch segments were undamaged as the adventitia was contained within the vein’s cushion of surrounding tissue (Fig 1). Conventional veins exhibited regions of vascular damage, including thinning of the media, removal of, or damage to, the adventitia and its vasa vasorum (Fig 1). Double-labeling studies confirmed that eNOS colocalized with the lumenal endothelial cells and that eNOS immunostaining was absent at regions of endothelial damage in conventional veins, whereas endothelial and eNOS staining was continuous in no-touch veins (Fig 2).
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Fig 1. Immunohistochemical identification of endothelial nitric oxide synthase (eNOS) in conventional and no-touch veins. (Top panels) Endothelial nitric oxide synthase identified by immunohistochemistry (red staining) on representative transverse sections of conventional and no-touch vein segments from the same patient undergoing coronary artery bypass graft surgery. Dense staining is associated with adventitial vasa vasorum (ADV [arrows]) and tunica media (TM). In no-touch vein segments, these structures remain intact, whereas they are removed or damaged in conventional segments. In addition, the TM is thinner in conventional segments owing to high-pressure distension. (Middle panels) Medial (TM) and adventitial (ADV) immunostaining of conventional and no-touch vein segments. Much of the adventitia has been removed in conventional segments, but remains intact in no-touch veins, where there is pronounced eNOS immunostaining associated with the vasa vasorum. (Bottom panels) Endothelial nitric oxide synthase immunostaining is absent at regions of denudation caused by distension of conventional vein segments (arrows) whereas immunostaining in no-touch segments lines the vessel lumen and is associated with an intact endothelium. Scale bar = 1 mm for top two panels and 250 µm for lower four panels.
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Fig 2. Endothelial-dependent endothelial nitric oxide synthase (eNOS) immunostaining in vein segments. Immunofluorescence micrographs of endothelial cells (CD31, red) and eNOS (green) on conventional (left) and no-touch (right) veins. Double labeling confirms that eNOS is associated with the lumenal endothelium and shows a pronounced absence of eNOS at regions of denudation in the conventional vein segments (arrows). Scale bar = 50 µm.
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The immunohistochemical data was supported by Western blot analysis that showed that both CD31 and eNOS protein expression were significantly reduced in conventional compared with no-touch veins (Fig 3B and 3C). More importantly, perhaps, was the observation that eNOS activity (NO "release"), as assessed by the citrulline assay, of conventional saphenous vein segments was significantly reduced compared with no-touch segments (p < 0.05; Fig 3D).
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Fig 3. Expression of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) release in human saphenous vein grafts. (A) Representative autoradiograms of Western blots of CD31 and eNOS protein expression in conventional (CONV) and no-touch (NT) vein segments from 3 patients normalized to ß-actin. (B, C) Histograms representing densitometric analysis of Western blots showing a significant reduction in both CD31 (n = 5) and eNOS (n = 8) protein expression in conventional compared with no-touch veins. (D) Histogram representing eNOS "activity" as assessed by the citrulline assay. There was also a significant reduction in conventional compared with no-touch vein segments (n = 8). Data are expressed as mean ± SEM. Paired t test, *p less than 0.05.
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Comment
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Despite the internal mammary artery being the vessel of choice for CABG, the saphenous vein is the most commonly used conduit as a bypass graft [15]. The rate of vein graft failure is high, with reports of as many as 15% grafts failing in the first month, 30% in the first year, and more than 50% within 10 years [1]. The saphenous vein was introduced as a bypass graft in the late 1960s [16], and problems associated with endothelial damage during graft preparation were soon recognized. In a canine vein graft model, distension caused endothelial cell involution, subendothelial fibrous, or myoepithelial proliferation within 2 to 4 weeks of surgery [17]. The authors concluded, "preimplant distension of vein grafts to overcome spasm should be employed sparingly as it adversely affects the endothelium, accelerates development of degenerative changes and early thrombotic complications." While most experimental studies into distension-induced vascular damage have been performed controlling pressure with a manometer, the (unmeasured) "manual pressure distension" commonly applied to the saphenous vein graft during CABG is believed to have detrimental consequences for graft patency [18]. A study into the effects of distension pressure on cell proliferation and apoptosis in human saphenous veins used pressures of 350 to 400 mm Hg [13], based on previous evidence that the average peak distension pressure required to overcome spasm was 480 mm Hg [14].
Damage is not confined to the lumenal endothelium during vein harvesting but also to all vessel layers, ranging from exposure of the intimal basement membrane, intimal tears and flaps, medial edema, fibrosis, and aneurysm formation to loss of adventitial vasa vasorum and vein sclerosis [11, 19–21]. Within these layers, a number of cells are affected by trauma caused during vein harvesting. For example, endothelial denudation and ultrastructural shape changes of endothelial cells have been reported, mainly caused by high-pressure distension [19, 22, 23]. Furthermore, altered medial VSMC morphology has been described in conventionally prepared saphenous veins, including signs of nuclear division, an early indicator of VSMC proliferation [24].
Many cells affected by vein preparation during CABG either synthesize, or are targets for, locally released NO [5]. Preservation of endogenous NO levels, by minimizing endothelial damage during harvesting, may prevent spasm when using atraumatic techniques [10]. This "protective" mechanism may also be maintained during the early postoperative period, counteracting any effects of endogenous vasoconstrictors to which the graft is highly sensitive [10, 22]. As long as 1 week after CABG, surgical preparation that results in endothelial injury causes platelet aggregation at the exposed intimal surface and thrombotic occlusion [11, 19]. As an inhibitor of platelet adhesion and activation [5], NO is beneficial in reducing early graft failure. In addition, NO promotes endothelial cell migration and proliferation [25], which may lead to a more rapid reendothelialization of the graft, thus reducing the period during which it is vulnerable to thromboses [10].
As well as platelet aggregation, intimal adhesion of neutrophils and monocytes occurs, cells releasing a range of factors that stimulate VSMC proliferation and migration through the internal elastic lamina, leading to neointimal formation [19]. Accumulation of VSMC and extracellular matrix in the intima also takes place in response to exposure of the graft to ischemia-reperfusion, arterial pressure, and shear stress [26]. Reperfusion injury reduces both basal and stimulated NO release and attenuates vasodilatation in response to agonists acting through eNOS, such as acetylcholine [27]. Vascular injury and increased stresses to which the vein is exposed result in a reduction in the biological effects of NO and a liberation of growth factors causing neointimal hyperplasia, reduced lumen diameter, and decreased coronary blood flow. Nitric oxide limits this process by inhibiting VSMC proliferation as well as inducing apoptosis [28]. Vein grafts treated with L-arginine exhibit reduced neointimal thickening associated with an elevation of NO levels [29].
After early signs of neointimal thickening, macrophages appear, and beyond 3 years the formation of superimposed atheromatous plaques results in further narrowing of the lumen, with graft failure often being due to plaque rupture and thrombotic occlusion [19]. The suggestion that endothelial damage, reduced eNOS bioactivity, and impaired NO release are involved in atherosclerosis is supported by experiments using eNOS knock-out mice in which L-arginine has beneficial effects in atherosclerosis and conditions of disturbed shear stress [30]. Flow-induced disturbances on NO levels and atherogenesis have been described where vasodilatation at branches of the vascular system, such as the coronary arteries, is impaired and associated with down-regulation of NOS [31]. In human endothelial cells, NOS expression is down-regulated, and increased protein expression of proatherogenic transcriptional factors is reversed by L-arginine administration [32].
We have previously shown that endothelial integrity of no-touch vein segments is maintained, whereas there are regions of endothelial denudation in conventional vein segments [7, 10]. This was confirmed to be an effect of distension since the lumen of nondistended conventional veins was thrown into folds, similar to no-touch segments, with the endothelium exhibiting minimal damage [10]. In the present study, we have identified a significant reduction in eNOS in conventional compared with no-touch veins that is accompanied by a concomitant reduction in NO "release." Of particular interest is that the reduction in NO release caused by surgical trauma shown in our study is comparable to the reduced basal and induced NO levels described in distended human saphenous vein segments determined using an NO-sensitive electrode [8]. Although it may be surprising that short-term distension elicits these marked alterations in the NO pathway, similar acute effects on vein graft material have been recently described. For example, distension of harvested human saphenous vein induces phosphorylation of p38 mitogen-activated protein kinase [33], a factor associated with signalling molecules and growth factors released from apoptotic cells that contribute to the proliferative responses characteristic of graft failure [34]. There is also evidence that short-term exposure of human saphenous vein segments to arterial flow increases maximum tension and sensitivity to vasoconstrictors [35], possibly because of removal of the "protective" action of endogenous NO [19]. This increased sensitivity is due to circumferential stretching of the vein’s VSMC, as these changes are reversed by the placement of an external stent [35].
Although the main focus of our study was into the effect of conventional harvesting on lumen-derived endothelial NO, there are a number of other potential sources of NO that are maintained when using atraumatic harvesting techniques. In addition to denudation of the lumenal endothelium and reduced NO levels caused by distension, the outermost layer of the saphenous vein is either removed or damaged when harvesting by conventional CABG. Using ß-nicotinamide adenine di-nucleotide phosphate-diaphorase histochemistry, prominent NOS staining has been described in regions of the adventitia of no-touch vein segments, much of which is associated with the vasa vasorum [10]. Using an isoform-specific antibody, we provide evidence that the adventitia exhibits strong eNOS immunostaining, a high proportion being to the vasa vasorum. The functional relevance of this observation is unclear, although there is considerable evidence that occlusion of, or damage to, this microvascular network, is involved in neointimal hyperplasia and atherosclerosis [36]. Preservation of the vasa vasorum is suggested to increase vein graft patency [20], and this may be accomplished by retaining the adventitia during surgical preparation of the saphenous vein for CABG [19].
Our study suggests that eNOS-derived NO plays a role in the improved patency of vein grafts removed with minimal damage. A number of other contributing factors are likely to be involved. It has been shown that placement of a loose-fitting external stent reduces neointimal hyperplasia and graft occlusion in a porcine saphenous vein-carotid artery interposition model [37]. Beneficial effects of perivenous support have also been described in human saphenous veins perfused at different pressures in vitro, where external stenting or perivascular application of fibrin glue have been shown to reduce vessel hyperreactivity [35, 38] and vascular damage [36]. It is possible that, apart from preserving tissue sources of NO, there is a mechanical contribution of the cushion surrounding no-touch vein grafts where it acts as a "biological stent" [1, 10]. By buffering the vein graft, once exposed to coronary arterial conditions, the stentlike properties of the vein’s surrounding tissue would be expected to reduce the effects of NO-releasing stimuli such as pulsatile pressure changes and shear stress. Rather than applying a synthetic external stent to the vein at the time of bypass grafting, a similar beneficial effect might be achieved by leaving the cushion of surrounding tissue intact while harvesting the vein [1, 2].
In conclusion, current methods of harvesting the saphenous vein for CABG cause considerable damage to the vessel, particularly to regions exhibiting high levels of eNOS and the potential to release NO. We believe that, by reducing vascular injury using atraumatic surgical techniques, tissue sources of NO are maintained and that this will result in improved graft performance.
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Acknowledgments
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We are grateful to Mats Karlsson, Alexandra Kolaric, and Laila Örtensjö, Department of Pathology, for their help in tissue collection. We also thank Derek Filbey for early discussions in the planning of this study. This work was supported by British Heart Foundation Project Grant No. PG/2002221 to Dr Michael R. Dashwood. Doctors Xu Shi-Wen, David J. Abraham, and Audrey Dooley acknowledge support from the Arthritis Research Council.
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Abstract
Introduction
