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Academic Medical Center, University of Amsterdam, Department of Medical Physics and Cardiovascular Research Institute, 1100 DE Amsterdam, The Netherlands
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
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We developed an organoid culture technique to study the mechanisms involved in arterial remodeling. Resistance arteries were isolated from rat cremaster muscle and mounted in a pressure myograph at 75 mmHg. Vessels were studied during a 4-day culture period in DMEM with either 2% albumin, 10% heat-inactivated FCS (HI-FCS) or 10% dialyzed HI-FCS (12 kDa cut off) added to the perfusate. The albumin group showed a gradual loss of endothelial function and integrity, whereas smooth muscle agonist and myogenic responses were retained. No remodeling was observed. Vessels cultured in the presence of serum showed a progressive constriction. Smooth muscle responses and substance P-induced endothelium-dependent dilation were maintained. An inward remodeling of 17 ± 4% in the HI-FCS group and 26 ± 3% in the dialyzed HI-FCS group was found, while media cross-sectional areas were unchanged. These data show that pressurized resistance arteries can be maintained in culture for several days and undergo eutrophic remodeling in vitro in the presence of high molecular weight serum factors.
vascular smooth muscle; pressure myograph; growth factors; endothelium; myogenic response
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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PERIPHERAL RESISTANCE and local tissue perfusion depend on both the structure and contractile activation of the resistance vasculature. Consequently, pathological alterations in tone and structure may lead to chronic ischemia as well as hypertension. An increase in the ratio between wall thickness and lumen diameter is found in human essential hypertension and various animal models of hypertension (14). This alteration can be the result of growth and/or the rearrangement of existing materials. The latter is referred to as eutrophic remodeling (21). The mechanisms controlling resistance vessel caliber are only partly understood. Thus the causality of relations between blood pressure, vascular tone, and vessel wall remodeling and hypertrophy remain the subject of ongoing discussion. Over the years the in vitro study of blood vessels (26-28) has proven to be a very useful tool in the unraveling of mechanisms involved in acute control of tone. It could therefore be envisioned that the study of vessels in organoid culture over longer periods of time similarly will improve our understanding of chronic control of diameter, reactivity and wall thickness. Some studies on vessels in organoid culture have been published. With the use of isometrically mounted renal arteries, DeMey et al. (10) showed that tissue culture itself impairs constrictor responses to some agonists, whereas serum was found to induce constriction and increase DNA synthesis. Lindqvist et al. (19) reported that unloaded rings of rat tail artery show an impaired contractility after a 4-day incubation period with FCS. Mechanical loading conditions may well be of major importance when studying in vitro cultured segments. The technique that most closely mimics the in vivo situation in this respect is the cannulated vessel setup. This approach does not in itself impose mechanical deformation of the vessel wall, which could interfere with the orientation of its structural elements and influence structural adaptation. A further advantage of the cannulated vessel setup is that pressure and flow can be controlled independently.
Bardy et al. (3) developed an organ culture system in which segments of rabbit aorta are pressurized and perfused for several days. These authors studied the effects of pressure and flow on DNA synthesis, matrix proteins, and smooth muscle marker proteins in rabbit aorta (3, 4, 7). Yet, no studies have been reported on cannulated resistance vessels in culture. Therefore, we aimed to develop an organoid culture system in which functional as well as structural adaptations of resistance arteries to mechanical parameters can be studied. For this purpose, we used cannulated resistance arteries from rat cremaster muscle. We report here on changes in smooth muscle and endothelial function, depending on composition of the incubation medium. Most importantly, we found that resistance arteries are capable of eutrophic remodeling in vitro. This structural change may be mediated by growth factors present in serum and relate to their contractile properties.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Male Wistar rats (250-350 g) were decapitated after sedation with 100% CO2, in accordance with institutional guidelines. Cremaster muscles were excised and placed in cold physiological saline solution composed of (in mM) 119 NaCl, 4.7 KCl, 1.18 KH2PO4, 1.17 MgSO4, 25 NaHCO3, 1.6 CaCl2, 0.026 EDTA, 5.5 glucose, and 10 HEPES. A 6- to 8-mm-long segment of the first order arteriole was dissected and cut into two pieces. One piece was fixed for 30 min in a mixture of 4% paraformaldehyde and 1% glutaraldehyde in 0.1 M phosphate buffer for histology or electron microscopy. The other segment was mounted in a pressure myograph under sterile conditions. The segment was stretched to its in situ length and kept at this length during the experiment. The vessel was superfused with DMEM containing penicillin (100 IU/ml) and streptomycin (0.1 mg/ml) that was recirculated from a 50-ml reservoir and refreshed daily. The solution was equilibrated with 19% O2, 76% N2, and 5% CO2, pH 7.4. Vessels were pressurized using an electro-pneumatic converter (model T5200, Fairchild) to 75 mmHg and kept at 34°C, the in vivo temperature of the cremaster muscle. Images were obtained using a ×10 objective and a monochrome charge-coupled device camera (512 × 582 pixels). Images were digitized with a framegrabber (model DT3152, Data Translation) and analyzed with Image-Pro Plus software (Image-Pro Plus version 3.0, Media Cybernetics).
Protocol.
Vessels were studied during a 4-day culture period under three
different conditions. In group 1, the vessel perfusate
consisted of DMEM + 2% BSA. In group 2, the perfusate
contained 10% heat-inactivated FCS (HI-FCS) in DMEM, and in group
3 the perfusate contained 10% dialyzed, HI-FCS in DMEM.
Heat-inactivation was performed by heating serum to 56°C for 30 min. This procedure prevents complement-induced attenuation of
endothelial function (9, 18). Serum was dialyzed to remove small
contractile factors. Dialysis was done against 0.9% NaCl for 24 h
using a cellulose membrane with a 12-kDa cut off. Experimental
protocols were similar for each group. On day 1, before the
segments developed spontaneous tone, a passive pressure-diameter relation between 25 and 125 mmHg was determined. After an equilibration period of 30 min, spontaneous tone had developed and an active pressure-diameter relation was obtained between 25 and 125 mmHg. Each
day, responses to endothelium-dependent dilatory agonists ACh
(10
6 M) and substance P (108 M)
were tested. Also, the contractile response to serotonin (3 × 107 M) was tested. In very deeply constricted
vessels, serotonin was added during dilation with substance P
(108 M). This way, we were able to assess the
serotonin effect with sufficient resolution and without the limitation
of complete closure of the vessel. In pilot experiments, the initial
level of tone did not affect the serotonin response as long as complete
closure was prevented. On day 4, an active pressure-diameter
relation was obtained between 25 and 125 mmHg as well as a passive
pressure-diameter relation after incubation for 30 min with
Ca2+-free PSS containing 10 mM EGTA and
104 M papaverin.
Histology.
After fixation, vessel segments were embedded in 15% gelatin (in PSS)
and rapidly frozen in liquid nitrogen. Tissues were sectioned using a
cryotome at 
20°C. Sections of 8 µm thickness were stained
with either toluidine blue or picosirius red, dehydrated in a graded
series of alcohol and embedded in mounting medium (Entellan, Merck).
Media cross-sectional areas were determined with Image-Pro Plus
software from three sections of each preparation and averaged.
Electron Microscopy. Tissues were rinsed in 0.1 M phosphate buffer, pH 7.4, and stained in 1% OsO4. After dehydration in a graded series of alcohol, vessels were embedded in Epon. Thin sections were cut on an ultramicrotome equipped with a diamond knife. Sections were stained with uranyl acetate and lead citrate and examined with an electron microscope.
Chemicals. DMEM, penicillin, and streptomycin were purchased from Life Technologies. FCS was obtained from Boehringer. All salts were obtained from Merck. Vasoactive compounds and bovine albumin were from Sigma.
Statistical analysis. Data are expressed as means ± SE where n is the number of arterial segments studied. A repeated-measurement ANOVA followed by a post hoc Dunnett t-test was performed to determine the significance of differences between days. A paired t-test was used for all other comparisons. Differences were considered significant at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Spontaneous tone.
A total number of 18 vessels was included in the present study. Passive
diameters (at 75 mmHg) were similar for all three groups: 181 ± 6 µm for albumin (n = 6), 178 ± 8 µm for HI-FCS (n = 6), and 183 ± 5 µm for dialyzed HI-FCS (n = 6). All
vessels developed spontaneous tone during the equilibration period,
resulting in similar active diameters (at 75 mmHg): 113 ± 8, 110 ± 9, and 117 ± 5 µm for albumin, HI-FCS, and dialyzed FCS,
respectively. As shown in Fig. 1, the
segments in the albumin group partially lost tone on day 2,
regained tone on the third day and again partially lost tone on the
fourth day. Typically, rhythmic vasomotion appeared on the second or
third day and continued throughout the experiment. Vessels that were
cultured with HI-FCS showed a progressive increase in spontaneous tone.
Typically, a normal level of spontaneous tone was observed on day
1, which then gradually increased. This constriction was affected
by neither ketanserin (1 µM; n = 3), an inhibitor of
serotonin receptors, nor by losartan, an inhibitor of ANG II receptors
(10 µM; n = 3), when added to the vessel at the end of the
experiment (data not shown). Also shown in Fig. 1, a similar
development of constriction was observed with dialyzed serum,
suggesting that small contractile factors present in serum were not
involved. Only washout of serum at the end of the experiment with fresh
DMEM resulted in a significant dilation of 35 ± 5 µm (n = 3). In both serum groups, vasomotion was less apparent but observed
occasionally during the second or third day.
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Responses to agonists.
As shown in Fig. 2, in the albumin group
responses to substance P gradually declined and were essentially lost
at day 4. In contrast, responses increased in the HI-FCS group.
Responses were significantly increased on day 3 compared with
day 1. Similarly, with dialyzed HI-FCS responses were
significantly increased on days 2 and 3.
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Active pressure-diameter relations.
As shown in Fig. 5, all segments displayed
a myogenic pressure-diameter relationship on day 1. Thus
vessels distended in the lower pressure range and constricted at higher
pressures. In the albumin group, the pressure-diameter relation was not
significantly altered on day 4. In both serum groups, a
downward shift of the pressure-diameter relation was observed. As shown
in Fig. 5B, the increased constriction was reflected over the
whole pressure range, indicating that myogenic reactivity was
preserved. Diameters were significantly smaller at each pressure level
for day 4 versus day 1.
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Passive pressure-diameter relations.
Passive pressure-diameter relations were obtained at the start and at
the end of each experiment. As shown in Fig.
6A, the relationship was unchanged
after a 4-day culture period in the albumin group. However, vessels
that were cultured in the presence of either HI-FCS or HI-dialyzed FCS
showed a marked decrease in inner diameters over the whole pressure
range (Fig. 6B). For instance, at 75 mmHg diameters were
decreased by 17 ± 4% in the HI-FCS group and by 26 ± 3%
in the dialyzed HI-FCS group.
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Histology.
Media cross-sectional areas were determined in freshly isolated vessel
segments and compared with their counterparts that underwent the
experimental protocol. Cross sections showed a clearly discernable
media surrounded by fibrous tissue consisting mainly of collagen, as
indicated by picosirius red staining. As shown in Fig.
7, media cross-sectional areas of control
and cultured segments were not statistically different in all groups.
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Electron microscopy.
Freshly isolated arterial segments showed a layer of endothelial cells
covering the luminal side of the vessel (Fig.
8A). As expected, the endothelial
cells were separated from the smooth muscle cells by a lamina elastica
interna. The media consisted of two layers of smooth muscle cells
orientated circumferentially. The adventitia contained collagen fibers
that were mainly orientated longitudinally and fibroblasts. Vessels
that were cultured in the presence of albumin showed nearly complete
absence of endothelial cells at day 4. This process appeared to
involve a detachment of endothelial cells from the luminal surface, as
shown in Fig. 8B. Here, a vessel is shown at the second day of
culture in the presence of albumin. Endothelial cells are still present
but only partly connected to the underlying tissue. In vessels that
were cultured with serum, endothelial cells were present at day
4, as illustrated in Fig. 8C. In general, the cells
appeared to be somewhat less elongated compared with control, and
occasionally small parts of the endothelial cells stretched out into
the vessel lumen. The internal elastic lamina was still present and the
orientation of the smooth muscle cells was unchanged in both the
albumin and serum groups. Smooth muscle cells did not show signs of
mitosis.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main findings of the present study are that 1) basal tone, myogenic reactivity and contractile responses remain present in vessels cultured in the absence or presence of serum. In the presence of serum, vessels 2) developed a progressive constriction, 3) showed a marked inward remodeling without a change in media cross-sectional area, and 4) maintained endothelium-dependent dilation.
Model characteristics.
Our ultimate goal is to have an in vitro technique for the study of
long-term control of resistance artery caliber and function. Although
on previous occasions vessels were cultured without mechanical load
(19), on needles (10), or in a wire myograph (23), our experiments were
done under physiological pressure. In this respect, the cannulated
vessel setup more closely mimics the in vivo situation while offering
the advantages of independent control of the chemical and physical
environment. It should be mentioned, however, that the current
technique is limited to vessels of 
50-100 µm in diameter
because smaller vessels are too difficult to isolate and
cannulate. The pressure utilized in the present study (75 mmHg) was based on in vivo pressure measurements in the cremaster muscle, reported by Meininger et al. (20). Roughly, pressure drops from
95 mmHg at the proximal end to 65 mmHg at the distal end in first order
arterioles such as used in the present study, indicating that these
vessels are true resistance vessels.
Responses to agonists. All vessels in the present study gradually lost their responsiveness to ACh. Since the serum-incubated vessels showed actually an increased responsiveness to another endothelium-dependent dilator, substance P, we conclude that the loss of the ACh response is not related to a general deterioration of endothelial function. More likely, a loss of muscarinic receptors may account for the observed results, in agreement with observations on cultured endothelial cells (25). Alternatively, downstream signaling pathways (2) might have been affected. In this respect, endothelial nitric oxide synthase levels have been shown to be affected by the presence of serum during culture of vascular segments (31). In the serum-free group, both ACh and substance P-induced responses were lost, in agreement with the electron microscopic images showing dissociating endothelial cells on day 2 and the absence of endothelial cells on day 4.
To test contractile responsiveness, serotonin was chosen since DeMey et al. (10) demonstrated that responses of wire-mounted segments to this agonist are preserved during culture, as opposed to phenylephrine and vasopressin responses. Serotonin receptors are present on smooth muscle and endothelium, which mediate constriction and dilation respectively (29). The increased contractile response to serotonin in the albumin group is in accordance with the loss of a counteracting effect of the endothelium. However, it is unclear why contractile responses in the dialyzed FCS group similarly increase, despite the presence of endothelial cells. Taken together, the agonist-induced responses in this study show that smooth muscle cells remain reactive for at least 4 days without serum in our setup, although serum is required for endothelial cell viability.Spontaneous tone. Basal tone (1) and myogenic responses (28) are fundamental properties of resistance vessels and of key importance for the control of organ perfusion. We therefore investigated whether both phenomena are maintained under culture conditions. In the presence of albumin alone, basal tone was slightly variable over the days, but was maintained up to day 4 (Fig. 1). Likewise, myogenic regulation was preserved (Fig. 5). Endothelial cells were absent by day 4. Thus in addition to the lack of effect of acute removal of the endothelium on myogenic responses (12), these data point out that the absence of the endothelium for a longer period does not affect this resistance artery property.
Vessels cultured in the presence of serum showed a progressive increase in constriction (Fig. 1). As was the case in the albumin group, myogenic regulation was maintained at day 4, albeit acting on a much deeper level of tone (Fig. 5B). Serum may contain small contractile factors like serotonin, which may induce constriction during organ culture (10). However, the contractile effect of serum was not prevented by serum dialysis, and inhibition of serotonin receptors with ketanserin was ineffective. Schiffers et al. (23) demonstrated that ANG II induces a slowly developing tonic increase in wall tension after a latency of 12 h in cultured renal arteries. However, involvement of ANG II can be prevented by serum dialysis, as the local renin-ANG system of the cremaster muscle depends on exogenous angiotensinogen (30). In addition, an inhibitor of ANG II receptors, when added to the vessel at the end of the experiment, had no effect on tone in our experiments. Possibly, the progressive increase in constriction may involve large molecular growth factors present in serum. In addition to their mitogenic effects, many growth factors have been shown to be potent vasoconstrictors. Platelet-derived growth factor was one of the first to be identified as a constrictor substance (6). Epidermal growth factor induces constriction in the DOCA-salt rat model, but not in control rats (13), and transforming growth factor-
constricts rat cremaster arterioles (17). In general, growth factor-induced constriction is associated with
a slow onset of contraction and is tonic in nature (5). Thus these
characteristics would fit the progressive increase in spontaneous tone
observed in our experiments.
Remodeling. We found a marked reduction in the passive inner diameter of arteries cultured in the presence of serum. In particular, a downward shift of the passive pressure-diameter relation was observed over the tested pressure range between 25 and 125 mmHg. No change in media cross-sectional area was found, indicating that a rearrangement of structural elements had occurred during the experiment. Such structural adaptation is referred to as eutrophic remodeling (21). The passive diameter of arteries at sufficiently high pressures is determined by the length, amount and orientation of collagen fibers (11). Therefore, these data point to a relatively rapid reorganization of the collagen fibers in the wall.
Remodeling was found both in HI-FCS and dialyzed HI-FCS, but not in serum-free cultured segments. The concomitant occurrence of constriction and remodeling raises the possibility that these effects are linked. There are basically two possibilities for such a linkage. First, both processes might share intracellular signaling pathways, and an agonist in serum could induce both effects. Recently, basic fibroblast growth factor (bFGF) has been implicated in remodeling in a mouse model. Treatment with an anti-bFGF antibody inhibited inward remodeling induced by ligation (8), whereas bFGF-deficient mice exhibit impaired smooth muscle contractility (32). Thus bFGF is implicated in both constriction and remodeling. The present coincidence of deep constriction and remodeling may therefore be attributed to the presence of bFGF or other growth factors in the serum. A second possibility, of potentially more importance, is that in the long run, passive characteristics follow the active diameter, irrespective of the mode of contraction. It is conceivable that a continuous rearrangement of extracellular matrix fibers occurs in the wall. When formed in a deeply constricted vessel, this would limit dilation and result in inward remodeling. It is, however, clear that this hypothesis requires a better understanding of matrix organization and turnover. In summary, we have developed an organoid culture technique for resistance arteries in which contractile responses and endothelial function are maintained for 4 days. This period is sufficient to observe substantial remodeling. This technique should provide a valuable tool for the study of tone and structure regulation under physiological conditions in vessels of a size relevant for control of organ perfusion and peripheral resistance.| |
ACKNOWLEDGEMENTS |
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We thank H. van Veen for technical assistance on the electron microscopy and M. van der Meer and R. van Driel for their contributions to the setup. We thank J. Perree for performing the picosirius red staining.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: E. VanBavel, Academic Medical Center, Dept. of Medical Physics, PO Box 22700, 1100 DE Amsterdam, The Netherlands (E-mail: e.vanbavel{at}amc.uva.nl).
Received 28 June 1999; accepted in final form 28 October 1999.
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METHODS
RESULTS
DISCUSSION
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E. N. T. P. Bakker, O. Sorop, J. A. E. Spaan, and E. VanBavel Remodeling of resistance arteries in organoid culture is modulated by pressure and pressure pulsation and depends on vasomotion Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2052 - H2056. [Abstract] [Full Text] [PDF]
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 A. Zeidan, I. Nordstrom, S. Albinsson, U. Malmqvist, K. Sward, and P. Hellstrand Stretch-induced contractile differentiation of vascular smooth muscle: sensitivity to actin polymerization inhibitors Am J Physiol Cell Physiol, June 1, 2003; 284(6): C1387 - C1396. [Abstract] [Full Text] [PDF]
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 Z. Ungvari, A. Csiszar, J. G. Edwards, P. M. Kaminski, M. S. Wolin, G. Kaley, and A. Koller Increased Superoxide Production in Coronary Arteries in Hyperhomocysteinemia: Role of Tumor Necrosis Factor-{alpha}, NAD(P)H Oxidase, and Inducible Nitric Oxide Synthase Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 418 - 424. [Abstract] [Full Text] [PDF]
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 M. J. Mulvany Small Artery Remodeling and Significance in the Development of Hypertension Physiology, June 1, 2002; 17(3): 105 - 109. [Abstract] [Full Text] [PDF]
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 H. Blain, I. Abdelmouttaleb, J. Belmin, A. Blain, J. Floquet, J.-L. Gueant, and C. Jeandel Arterial Wall Production of Cytokines in Giant Cell Arteritis: Results of a Pilot Study Using Human Temporal Artery Cultures J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2002; 57(4): M241 - 245. [Abstract] [Full Text] [PDF]
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 A.'a. Zeidan, I. Nordstrom, K. Dreja, U. Malmqvist, and P. Hellstrand Stretch-Dependent Modulation of Contractility and Growth in Smooth Muscle of Rat Portal Vein Circ. Res., August 4, 2000; 87(3): 228 - 234. [Abstract] [Full Text] [PDF]
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C. L. Buus, F. Pourageaud, G. E. Fazzi, G. Janssen, M. J. Mulvany, and J. G.R. De Mey Smooth Muscle Cell Changes During Flow-Related Remodeling of Rat Mesenteric Resistance Arteries Circ. Res., July 20, 2001; 89(2): 180 - 186. [Abstract] [Full Text] [PDF]
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