© 1999 American Heart Association, Inc.
Vascular Biology |
Protection by Shear Stress From Collar-Induced Intimal Thickening
Role of Nitric Oxide
From Laboratorio di Farmacologia (G.M., S.P.), Istituto Superiore di Sanità, Rome; Istituto di Anestesia e Rianimazione (A.V.), Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome; Cattedra di Cardioangiologia Medica (A.U.F.), Centro Fisiologia Clinica e Ipertensione, University of Milan; CNR and IRCSS Ospedale Maggiore (A.U.F.), Milan, Italy.
Correspondence to Giuseppe Marano, MD, Laboratorio di Farmacologia, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail gmarano{at}iss.it
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Abstract |
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Abstract—Nitric oxide (NO) has potent relaxant and antiproliferative effects on vascular smooth muscle cells, which may represent an important antiatherosclerotic mechanism. Since one of the major stimuli for NO release is flow-related shear stress, we have investigated (1) the effect of increased shear stress on neointimal formation induced in the rabbit carotid artery by enclosing the vessel in a nonconstrictive silicone soft collar and (2) the role of NO in the antiproliferative effect of increased shear stress. Forty-three New Zealand White rabbits were used. High shear stress in the left common carotid artery (CCA) was induced by ligature of the contralateral right internal carotid artery; intimal thickening was produced by the positioning a nonconstrictive silicone soft collar around the left CCA. To evaluate the role of NO, NG-nitro-L-arginine methyl ester (L-NAME) was orally administered at a subpressor dose. In all rabbits, arterial blood pressure, heart rate, arterial diameters, and blood flow velocities of both CCAs were determined at days 0, 3, 7, and 14. At the end of the study, all rabbits were euthanized, and histological analyses were performed on both CCAs of each animal. The presence of the collar was associated with a marked degree of intimal hyperplasia (intimal/medial area ratio 29±3.0% in collared arteries compared with 3±0.7% in sham control [noncollared] arteries, P<0.001). The increase in blood flow almost completely inhibited neointimal formation and induced an increase in arterial diameter of
30%. The effects of increased
blood flow were reversed by the administration of L-NAME. In
conclusion, we demonstrate that in collar-induced intimal thickening, a
chronic increase in shear stress (1) almost completely inhibits intimal
thickening, and (2) this protective effect is mediated by NO
production.
Key Words: shear stress • intimal hyperplasia • collar model • nitric oxide • flow-dependent vasodilation • rabbits
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Introduction |
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Nitric oxide (NO) has potent relaxant and antiproliferative effects on vascular smooth muscle cells. These effects have been well documented in vivo and in vitro.1 2 3 4 5 It is believed that one of the major stimuli to NO synthesis and release from the arterial wall is the shear stress to which the vascular endothelial lining is subjected. Therefore, it is conceivable that a high blood flow/shear stress hemodynamic regimen may be associated not only with NO-dependent functional relaxation but also with inhibition of the intimal proliferative response to growth-promoting stimuli. For example, it was recently reported that high intra-arterial blood flow inhibits neointimal formation in graft- and balloon-induced intimal thickening models6 7 8 ; ie, neointimal formation is inhibited after the native endothelium is lesioned by various mechanical traumas. Although it was suggested that regenerated endothelial cells play a key role in this effect,7 it is to be considered that in deendothelialized vessels NO synthesis and release may be taken over by the smooth muscle cells themselves, probably as a consequence of their exposure to shear stress,9 and that the neoendothelium is functionally different from the original cell layer; ie, it has defective production of NO and prostacyclin.10 11 Thus, it is not yet known whether and by which mechanisms high blood flow is capable of inhibiting the intimal proliferative response to growth-promoting stimuli when the native endothelium is present.
The above premises prompted us to verify whether high flow and NO release may modulate the vascular proliferative response in the collar model of neointimal formation, ie, in a setting in which growth develops under the original, noninterrupted, nonregenerated endothelium. The goals of the present study were (1) to evaluate whether an increased blood flow/shear stress can inhibit collar-induced intimal thickening, with the increase in flow being obtained in the collared common carotid artery (CCA) by placing a ligature on the contralateral internal carotid artery, and (2) to establish whether the NO system is involved in inhibiting collar-induced growth, ie, whether and to what extent the administration of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) is able to reverse the protective effect of increased blood flow/shear stress on intimal thickening. Because of the controversial results previously reported,2 12 13 an additional goal of the present study was to further assess the changes in carotid artery diameter in response to large increases in blood flow.
To this aim, measurements of blood flow velocity and arterial diameter of experimental rabbits were obtained in both CCAs immediately before and after as well as at days 3, 7, and 14 after ligature of the right internal carotid artery, and histological studies were carried out after euthanizing the animals at day 14.
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Methods |
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Experimental Groups and Drug Treatments
The experiments were conducted in 43 male New Zealand White rabbits (Charles River, Italy) weighing 2.5 to 3.0 kg and complied with the recommendations of the Council of European Community (86/609/EEC) in all phases.
Forty rabbits were randomly divided into 5 groups of 8 rabbits each. In group 1 (collared+normal shear stress), rabbits were subjected to a nonconstrictive silicone soft collar application (see details in the next paragraph) in the left CCA, whereas the contralateral internal carotid artery was isolated but not ligated. In group 2 (collared+high shear stress), a collar was positioned around the left CCA; contralaterally, the right internal carotid artery was isolated and ligated. In groups 3 (collared+high shear stress+placebo) and 4 (collared+high shear stress+L-NAME treatment), the same surgical procedures as in group 2 were performed, but the animals additionally received drug vehicle or L-NAME (160 µg/mL in drinking water), respectively. This dose of L-NAME was chosen because it has been demonstrated in rabbits to be effective on the vascular wall without affecting arterial blood pressure.14 15 Treatment was started 7 days before collar application to obtain effective NO synthase inhibition at the time of the surgical procedure, and the treatment was continued for 14 days. In group 5 (sham control), both CCAs were exposed, and the left CCA was surgically manipulated in an identical fashion and for the same time as the carotid artery enclosed by the collar. All animals in each group underwent histological analysis.
In another experimental series, 3 rabbits underwent ligature of the right internal carotid artery. A telemetry probe (TL11 mol/L2-CXT-P50, Data Sciences Inc) was inserted in the femoral artery 7 days before vessel ligature to evaluate whether the surgical procedure used to increase blood flow in the left CCA produced significant changes in hemodynamic conditions during the entire period of study.
Surgical Procedures
Anesthesia was induced intramuscularly with
ketamine (10 mg/kg) and midazolam (0.1 mg/kg), and then
orotracheal intubation was attempted immediately after the rabbits lost
consciousness. A cuffed endotracheal tube (3.0-mm ID, D.A.R.) was
inserted into the trachea and connected to a respiratory ventilator
(model 7900, Ohmeda) set at a tidal volume of 10 mL/kg. The ventilatory
rate was adjusted to 30 to 35 breaths per minute to keep end-tidal
CO2 between 35 and 37 mm Hg. End-tidal
anesthetic and carbon dioxide levels were continuously monitored (gas
monitor, 5250 RGM, Ohmeda). Pancuronium bromide (0.1 mg/kg IV) was
injected to induce muscle relaxation and facilitate mechanical
ventilation. Anesthesia was maintained with end-tidal 1.8%
isoflurane (1minimum alveolar concentration) in a gaseous
mixture of nitrous oxide (N2O) and oxygen
(O2) (50/50% [vol/vol]). Body temperature and
lead II of the ECG were monitored continuously. A 24-gauge catheter
needle was inserted percutaneously into the marginal
ear vein, and an intravenous flow control system
(DIAL-A-FLO, Abbott) was attached to it. Lactated Ringer’s solution
was infused at 4 mL/kg per hour throughout the study. A 22-gauge
catheter needle was percutaneously inserted into the
central ear artery in all animals at days 0, 3, 7, and 14 to determine
arterial blood pressure and heart rate. Both CCAs were
exposed (groups 1 to 5), and the left CCA (groups 1 to 4) was enclosed
in a nonocclusive, biologically inert, silicone soft collar in
accordance with Soma et al.16 Briefly, longitudinally
split silicone collars (20-mm length, 1-mm wall thickness, 2x1-mm
contact length, 4-mm internal diameter at the center, and 1.9 mm
at either end) were placed around the left CCA, the external diameter
of which was smaller than the bore of the collar endings.
Histology and Histomorphometric Analysis
The rabbits were euthanized after 14 days with an overdose of
pentobarbital, and both CCAs from groups 1 to 5 were isolated and
excised. The left CCAs from groups 1 to 4 were divided into 3 regions:
a tract proximal to the collar, a midregion that had been surrounded by
the collar, and a tract distal to the collar. The specimens were fixed
for 2 hours in buffered formalin and embedded in paraffin. Cross
sections (5-µm thickness) were cut and stained with hematoxylin and
eosin and van Gieson-Weigert stain.
Histomorphometric analysis was performed by means of a semiautomatic image analyzer (Quantimet 500, Leica). The cross-sectional area of media and intima was measured at x10 magnification. Neointimal growth was evaluated in terms of intimal area and intimal-to-medial area ratio.
Carotid Ultrasonography and Measurement of Shear Stress
Under isoflurane anesthesia and continuous
hemodynamic monitoring, carotid ultrasonography was
performed in each rabbit along both CCAs at days 0 (before and 20
minutes after surgical procedure), 3, 7, and 14 with an Esaote AU3
Partner linear array probe (imaging at 7.5 MHz) and spectral
Doppler and color Doppler (at 5 MHz). In addition, the left CCA
was divided into 3 main regions for Doppler analysis, as
follows: (1) proximal to the collar (1 cm), (2) intermediate
arterial segment surrounded by the collar, and (3) distal
to the collar (1 cm). Blood velocities were measured with pulsed
Doppler at an angle of 60°, and internal vessel diameters were
obtained from 2-dimensional echocardiograms. Carotid blood flow was
calculated as the product of the lumen area
(
D2/4) and the Doppler-derived
time-velocity integral. To further confirm measurements obtained by the
ultrasonographic velocimetric and B-mode procedures, blood flow at days
0 and 14 was determined by ultrasonic flowmetry based on the
transit time principle (model 106, Transonic System). By assuming
laminar flow conditions, shear stress (
) at baseline and under
increased blood flow conditions was calculated with the
Hagen-Poiseuille approximation: =4
µQ/r3, where µ is the viscosity of rabbit
blood (considered to be constant and equal to 0.035 poise), Q is the
blood flow (mL/s), and r is the radius (cm) of the carotid artery.
Statistical Analysis
Data are expressed as mean±SE. The responses under different
experimental conditions were compared by using Student t
test or 2-way ANOVA. If a significant F value was obtained, the
Bonferroni test was used to assess specific differences between groups
(Statview 4.02 statistical package). The level of statistical
significance was set at P<0.05.
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Results |
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Ligating the right internal carotid artery to increase carotid blood flow in the left CCA did not alter mean arterial pressure (91±6.5 versus 90±7.1 mm Hg after versus before ligation) and heart rate (235±18 versus 230±22 bpm) in conscious nonrestrained rabbits. Therefore, the vascular responses to these procedures have to be attributed to changes in local hemodynamic conditions. It is also to be mentioned that with the rabbits under isoflurane anesthesia, blood flow was systematically found to be higher in the right CCA than in the left CCA (by
25%): as a consequence, in order to prevent this difference
in baseline hemodynamics from confounding the
interpretation of the results of the study, it was elected to
invariably place the collar on the same (left) side and, in turn, to
ligate the internal carotid artery on the right side.
Hemodynamic Responses to Increased Blood
Flow
No significant differences in hemodynamic
parameters and arterial diameters between the
different regions of the left CCA were observed, so the data from the
proximal and distal segments are not shown, and only the midcollar
figures are presented herein. Isoflurane anesthesia
was used, and arterial blood pressure, heart rate, carotid
diameter, mean flow velocity, mean blood flow, and mean wall shear
stress remained unchanged during the entire experimental protocol in
group 1 (collared, sham ligature) (Table 1
) and in group 5 (sham control group).
In groups 2, 3, and 4, the arterial blood pressure and
heart rate were similar to those obtained in group 1 and did not
significantly differ from those values obtained in conscious,
nonrestrained rabbits.
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In group 2 (data summarized in Table 2),
ligature of the right internal carotid artery caused blood flow in the
left CCA to markedly increase from 41.2±3.4 to 79±5.1 mL/min
(+91.7%, P<0.01) and the calculated wall shear stress to
increase from 59.7±5.5 to 117±5.5 dyne/cm2
(+96%, P<0.01); in spite of the dramatic
hemodynamic alterations, no acute (20-minute) increase
in left CCA diameter was observed. Such an increase was instead well
evident, and statistically significant, on day 3 as well as on the
later (7th and 14th) days of observation; its magnitude ranged from
25% to 30%. At the same time, the increase in blood flow was
maintained (Table 2), whereas wall shear stress significantly
decreased near (although not completely back to) control values.
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In group 3, which was experimentally identical to group 2 except for oral placebo administration, the hemodynamic and vascular responses to increased blood flow were, as expected, virtually identical to those obtained in group 2 and are not shown.
In group 4, L-NAME at the dose selected had no blood pressure–raising
effects at any time. After ligature of the right internal carotid
artery, blood flow in the left CCA and the calculated wall shear stress
were found to be increased significantly on day 0 and stayed elevated
through days 3, 7, and 14 (Table 3). Left
CCA diameter was unaffected acutely after right internal carotid artery
ligation, but at variance with groups 2 and 3, it failed to increase
throughout the later period of observation.
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In the right CCA from groups 2, 3, and 4, blood flow decreased by
67% (from 59±3.4 to 19±2.5 mL/min) 20 minutes after ligature of
the homolateral internal carotid artery and remained unchanged at days
3, 7, and 14. The diameter increased by 10% after the procedure
(2.0±0.05 versus 1.8±0.05 mm after versus before ligature) but
tended to decrease toward control values at days 3, 7, and 14.
Histological and Morphometric Analysis
At harvest, all the carotid arteries were patent and did not show
any abnormality on gross examination, except for a diffuse
periadventitial fibrous thickening in the region surrounded by the
collar.
Left CCAs of group 1 and L-NAME–treated group 4 showed a severe degree
of intimal hyperplasia in the region that had been surrounded by the
collar (Figure 1A). Intimal hyperplasia
consisted of a new growth of spindle-shaped cells and an extracellular
matrix lined by a continuous layer of endothelial
cells, either flat or swollen. Neither intimal inflammatory infiltrates
nor medial lesions were observed. The carotid segments that were not
enclosed in the collar did not show any intimal lesions. In groups 2
and 3, intimal hyperplasia was significantly reduced (Figure 1B). In the sham-operated left CCAs and right CCAs from all
groups, no noticeable changes could be detected (Figure 1C).
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On histomorphometric analysis, the neointimal areas
were 0.15±0.03, 0.04±0.003, 0.05±0.006, and 0.026±0.002
mm2 in groups 1, 2, 3, and 5, respectively; the
corresponding values of the intima/media area ratio were 29±3%,
8±2.7%, 9±3.1%, and 3±0.7% (P<0.01 group 1 versus
groups 2, 3, and 5 in all cases; Figure 2). In the L-NAME–treated animals of
group 4, intimal hyperplasia was again present; its degree was
similar to that observed in group 1 (neointimal area
0.16±0.03 mm2, intima/media area ratio
30±3%; Figure 2).
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Discussion |
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The major findings of the present study, in a model that allowed us to evaluate the effect of increased shear stress on the development of collar-induced intimal thickening in the presence of the original endothelium, are that (1) the increase in blood flow/shear stress prevents collar-induced intimal thickening, (2) this inhibitory effect is mediated by NO release, and (3) after 14 days, the increase in wall shear stress produces a significant enlargement of the left CCA, with the flow-dependent vasodilation also being mediated by NO release.
The inhibitory effect of high shear stress on the development of intimal hyperplasia has already been highlighted.6 7 8 However, these results were obtained in experimental models of intimal hyperplasia involving extensive denudation of the endothelium and significant trauma to the vessel wall. We report for the first time that this inhibitory effect also occurs in a model of intimal hyperplasia that develops under an original, nonregenerated, noninterrupted endothelium.
Although not definitively proven, the most likely explanation underlying our findings is that prevention of collar-induced intimal thickening by high flow was mediated by the endothelium. This is likely because the endothelial cell layer is the major sensor to changes in shear stress, and it subserves functions such as barrier regulation of permeability to platelet- and leukocyte-derived growth factors as well as production of growth-inhibitory substances,17 18 thus playing a key role in antagonizing neointimal formation.
This notion is strengthened by the second major result of the present study, ie, that the protective effect of high shear stress against neointimal formation is reversed by chronic inhibition of NO synthase. These data demonstrate that NO production is critical to the growth-inhibitory effect of high shear stress in collared arteries. In addition, our results are in line with the suggestion that NO production is modulated by flow and that NO inhibits intimal hyperplasia in vivo. In fact, it has been reported that the gene expression of NO synthase is regulated by flow.9 19 Furthermore, it has also been shown that administration of L-arginine (the precursor of NO) or of synthetic NO donors or the transfer of constitutive NO synthase gene into smooth muscle cells is capable of inhibiting intimal thickening in balloon-injured arteries and vein grafts.3 4 20 21 Moreover, Cayatte et al22 reported that chronic inhibition of NO production by L-NAME accelerates neointimal formation in cholesterol-fed rabbits.
The third significant result of the present study is that a
sustained increase in blood flow (3 to 14 days) produces a significant
enlargement of the CCA, which tends to normalize shear stress, and that
this effect is also related to NO production because the
enlargement of the artery was not observed in animals chronically
treated with a NO synthase inhibitor. This may be of
relevance in the debate concerning the effects of increased blood flow
on vascular remodeling: in rats the increase in shear stress has been
reported to induce aortic expansive remodeling 2 months after an
aortocaval fistula is opened,13 whereas in adult rabbits
the increase in blood flow in the right CCA by left-to-right carotid
anastomosis would not induce any compensatory enlargement after 2
months.12 On the other hand, Tronc et al2
have reported that NO synthase inhibition by
NG-nitro-L-arginine
blocks the arterial dilation induced by increased blood
flow in experimental arteriovenous fistulas in adult rabbits. These
controversial results could depend on differences in the technical
conditions under which data have been collected (ultrasonography versus
histomorphometric analysis) and/or in the experimental
protocol, species used, and timing of observations. Our findings are in
favor of the occurrence of significant dilation in response to enhanced
blood flow/shear stress, although they also indicate that the process
may have some degree of latency for the following reason: despite the
immediate increase in wall shear stress after internal carotid artery
ligation, the vasodilator effect was not immediately apparent and could
only be detected 
3 days later. This is in accordance with data
reported in the literature and could be due to development of a Venturi
effect within the left carotid axis in the early phases after ligature
of the contralateral internal carotid artery.13
A few additional aspects of our experiments are worthy of comment. First, chronic oral administration of L-NAME (160 µg/mL in drinking water) had no significant effect on systemic blood pressure measured in the anesthetized rabbit for up to 14 days of observation. These results are at variance with those reported in rats during chronic administration or in rabbits after acute intravenous administration.23 24 However, our data are consistent with previous reports14 15 showing that chronic oral administration of L-NAME at similar doses in rabbits has no effect on blood pressure. These discrepancies may be due to interspecies differences and/or to different routes of administration of L-NAME.
Second, among the possible limitations of the present study, it is to be mentioned that we based shear stress estimation on measurement of blood flow and arterial diameter by using a Hagen-Poiseuille flow approximation according to which shear stress is directly proportional to blood flow and inversely proportional to the cube of the vessel radius; although known not to be strictly valid for pulsatile flow, this approximation is widely accepted and used in the literature to calculate shear stress. A further problem relates to the fact that NO synthase inhibition by L-NAME is not specific to an isoform; because 2 major isoforms, constitutive and inducible, have been described, the isoform of NO synthase involved in the processes examined in our experiments remains to be determined.
In conclusion, our results demonstrate that in a rabbit model of intimal hyperplasia that develops in the presence of the original nonmechanically lesioned endothelium, a chronic increase in blood flow and shear stress (1) inhibits intimal thickening and (2) produces a significant flow-dependent enlargement of the left CCA. Both effects are mediated by stimulation of NO production.
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Acknowledgments |
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The authors wish to thank Stefano Fidanza and Adriano Urciuoli for their excellent technical assistance.
Received January 14, 1999; accepted March 26, 1999.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Gardiner SM, Compton AM, Bennett T, Palmer RM, Moncada S. Control of regional blood flow of endothelium-derived nitric oxide. Hypertension,. 1990;15:486–492.
2.
Tronc F, Wassef M, Esposito B, Henrion D, Glagov S,
Tedgui A. Role of NO in flow-induced remodeling of the rabbit common
carotid artery. Arterioscler Thromb Vasc Biol. 1996;16:1256–1262.
3. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989;83:1774–1777.
4. McNamara DB, Bedi B, Aurora H, Tena L, Ignarro LJ, Kadowitz PJ, Akers DL. L-Arginine inhibits balloon catheter-induced intimal hyperplasia. Biochem Biophys Res Commun. 1993;193:291–296.[Medline] [Order article via Infotrieve]
5. Marks DS, Vita JA, Folts JD, Keaney JF, Welch GN, Loscalzo J. Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide. J Clin Invest. 1995;96:2630–2638.
6.
Kohler TR, Kirkman TR, Zierler BK, Kraiss LW, Clowes
AW. Increased blood flow inhibits neointimal hyperplasia in
endothelialized vascular grafts. Circ Res. 1991;69:1557–1665.
7.
Sugiyama T, Kawamura K, Nanjo H, Sageshima M, Masuda
H. Loss of arterial dilation in the
reendothelialized area of the flow-loaded rat common
carotid artery. Arterioscler Thromb Vasc Biol. 1997;17:3083–3091.
8.
Kraiss LW, Kirkman TR, Kohler TR, Zierler BK, Clowes
AW. Shear stress regulated smooth muscle proliferation and
neointimal thickening in porous
polytetrafluoroethylene grafts.
Arterioscler Thromb. 1991;11:1844–1854.
9.
Papadaki M, Tilton RG, Eskin SG, McIntire LV. Nitric
oxide production by cultured human aortic smooth muscle cells:
stimulation by fluid flow. Am J Physiol. 1998;274:H616–H626.
10. Weidinger FZ, McLenachan JM, Cybulsky MI, Gordon JB, Rennke HG, Hollenberg NK, Fallon JT, Ganz P, Cooke JP. Persistent dysfunction of regenerated endothelium after balloon angioplasty of rabbit iliac artery. Circulation. 1990;81:1677–1690.
11. Saroyan RM, Roberts MP, Light JT, Chen IL, Vaccarella MY, Bang DJ, Kvamme P, Singh S, Scalia SV, Kerstein MD, Kadowitz PJ, McNamara DB. Differential recovery of prostacyclin and endothelium-derived relaxing factor after vascular injury. Am J Physiol. 1992;262(Heart Circ Physiol 31):H1449–H1457.
12. Brownlee RD, Langille BL. Arterial adaptations to altered blood flow. Can J Physiol Pharmacol. 1991;69:978–983.[Medline] [Order article via Infotrieve]
13. Ben Driss A, Benessiano J, Poitevin P, Levy BI, Michel J-B. Arterial expansive remodeling induced by high flow rates. Am J Physiol. 1997;272(Heart Circ Physiol 41):H851–H858.
14.
Naruse K, Shimizu K, Muramatsu M, Toky Y, Miyazaki Y,
Okumura K, Hashimoto H, Ito T. Long-term inhibition of NO synthesis
promotes atherosclerosis in the
hypercholesterolemic rabbit thoracic aorta: PGH2 does
not contribute to impaired endothelium-dependent
relaxation. Arterioscler Thromb. 1994;14:746–752.
15. Holm P, Korsgaard N, Shalmi M, Andersen HL, Hougaard P, Skouby SO, Stender S. Significant reduction of the atherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits. J Clin Invest. 1997;100:821–828.[Medline] [Order article via Infotrieve]
16.
Soma MR, Donelli E, Parolini C, Mazzini G, Ferrari C,
Fumagalli R, Paoletti R. HMG coA reductase inhibitors: in
vivo effect on carotid intimal thickening in
normocholesterolemic rabbits. Arterioscler
Thromb. 1993;13:571–578.
17. Ross R. Atherosclerosis: a defense mechanism gone away. Am J Pathol. 1993;143:985–1002.
18.
Traub O, Berk BC. Laminar shear stress: mechanisms by
which endothelial cells transduce an atheroprotective
force. Arterioscler Thromb Vasc Biol. 1998;18:677–685.
19.
Ziegler T, Silacci P, Harrison VJ, Hayoz D. Nitric
oxide synthase expression in endothelial cells exposed
to mechanical forces. Hypertension. 1998;32:351–355.
20.
von der Leynen HE, Gibbons GH, Morishita R, Lewis NP,
Zhang L, Nakajima M, Kaneda Y, Cooke JP, Dzau VJ. In vivo gene
transfer to prevent neointima hyperplasia after vascular
injury: effect of overexpression of constitutive nitric oxide synthase.
Proc Natl Acad Sci U S A.. 1995;92:1137.
21. Davies MG, Kim JH, Dalen H, Makhoul RG, Svendsen E, Hagen PO. Reduction of experimental vein graft intimal hyperplasia and preservation of nitric oxide-mediated relaxation by the nitric oxide precursor L-arginine. Surgery. 1994;116:557–568.[Medline] [Order article via Infotrieve]
22.
Cayatte AJ, Palacino JJ, Horten K, Cohen RA. Chronic
inhibition of nitric oxide production accelerates
neointima formation and impairs endothelial
function in hypercholesterolemic rabbits.
Arterioscler Thromb. 1994;14:753–759.
23. Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest. 1992;90:278–281.
24. Schwarzacher S, Raberger R. L-NG-nitro-arginine methyl ester in the anesthetized rabbit: venous vasomotion and plasma levels. J Vasc Surg. 1992;29:290–292.
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