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1 Department of Physiology and 2 Departments of Cell Biology and Ophthalmology, New York Medical College, Valhalla, New York 10595
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The cytoskeleton is believed to have an important
role in the structural and functional integrity of endothelial cells.
The role of the endothelial cytoskeleton, specifically microtubules, in
the mediation of flow-induced dilation of arterioles has not yet been
studied. Thus the aim of our study was to investigate the role of
microtubules in the endothelial mechanotransduction of flow-induced
dilation of isolated gracilis arterioles of the rat. The active
diameter of arterioles at a constant perfusion pressure (80 mmHg) was
~63 µm, whereas their passive diameter (Ca2+-free
solution) was ~119 µm. At a constant pressure, increases in flow of
the perfusate solution (from 0 to 10 and from 10 to 20 µl/min)
elicited increases in diameter up to ~95 µm (~53%
increase). Intraluminal administration of nocodazole at
concentrations of 5 × 10
9 and 5 × 108 M had no discernible effects on the structure of
endothelial microtubules or on flow-induced dilation, whereas it
disassembled microtubules and eliminated flow-induced dilation at a
concentration of 5 × 107 M. At this higher
concentration, however, the basal diameter and dilations to
acetylcholine (108 M), sodium nitroprusside
(107 M), arachidonic acid (5 × 106 M), and prostaglandin E2
(108 M) were unaffected. Colchicine (5 × 107 M) also disassembled microtubules and eliminated
flow-induced dilation. We concluded that, in isolated arterioles, the
integrity of the endothelial cytoskeleton is essential for the
transduction of the shear stress signal that results in the release of
endothelial factors evoking dilation.
isolated arterioles; nocodazole; colchicine; wall shear stress
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE VASCULAR ENDOTHELIUM has a pivotal role in sensing alterations of hemodynamic forces (6, 20, 29). In vivo (10, 15, 16) and in vitro studies (18, 19) have demonstrated that increases in fluid shear stress elicit changes in the function of the endothelium, resulting in the release of vasoactive factors affecting the tone of arteriolar smooth muscle. The resultant increase in the diameter of vessels decreases wall shear stress, thereby reducing the signal sensed by the endothelium (16, 18). In recent years, studies of cultured endothelial cells have revealed some of the signal transduction pathways that may be activated by shear stress. Among these, the participation of ion channels (1) and biochemical second messengers such as tyrosine kinases (4), G proteins (8), and phosphorylation of endothelial nitric oxide (NO) synthase (2) were suggested. Several studies of cultured endothelial cells have indicated that elements of the cytoskeleton are important not only to maintain the structural integrity of endothelial cells but also to regulate the activity of various enzymes (22, 24, 26) involved in the synthesis of endothelium-derived vasoactive factors, such as NO and prostaglandins, known to mediate flow-dependent dilation (5, 17-19). In these experiments, however, the regulation of wall shear stress by changes in arteriolar diameter, as elicited by factors released from the endothelium (an important physiological response), could not be observed. Moreover, in these studies, fluid shear stress above the cells was maintained for an extended period of time to assess changes in the gene expression of various enzymes, whereas the acute vascular response to shear stress is likely to be dependent on changes in enzyme activity that take place within seconds.
Thus the goal of the present study was to test the hypothesis that the endothelial cytoskeleton, specifically microtubules, has a role in the mediation of shear stress-induced dilation of skeletal muscle arterioles.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Preparation of isolated arterioles. Experiments were conducted on isolated arterioles of rat gracilis muscle. All protocols were approved by the Institutional Animal Care and Use Committee of New York Medical College and conform to the current guidelines of the National Institutes of Health and the American Physiological Society for the use and care of laboratory animals. Male Wistar rats, 12-15 wk old (300-350 g body wt), were anesthetized with an intraperitoneal injection of pentobarbital sodium (Nembutal, 50 mg/kg). The gracilis muscle was exposed by an incision of the skin (17). The muscle was removed and placed in a petri dish containing cold (0-4°C) physiological salt solution (PSS) at pH 7.4. Rats were then killed with an overdose of Nembutal. The PSS contained (in mM) 145 NaCl, 5 KCl, 2 CaCl2, 1 MgSO4, 1 NaH2PO4, 5 dextrose, 2 pyruvate, 0.02 EDTA, and 3 MOPS. The tissue was pinned to the Silastic (transparent) bottom of the dish and allowed to equilibrate for 15 min.
The isolation procedure of second-order arterioles was described previously (17). Briefly, with the use of microscissors and an operating microscope (Olympus), ~1-mm-long segments of the arterioles were isolated from the gracilis muscle and surrounding tissue and transferred to the vessel chamber, which contained two glass micropipettes and PSS at room temperature. Isolated arterioles were cannulated on the pipettes and suffused with bicarbonate-buffered PSS to maintain pH at 7.4 (17). After several minutes of perfusion, the distal outflow cannula was closed, and pressure was slowly increased to 80 mmHg. Vessels were warmed slowly to 37°C (YSI temperature controller, Yellow Springs Instruments) and allowed to equilibrate for 60 min. The PSS used to perfuse and superfuse the vessels contained (in mM) 118 NaCl, 5 KCl, 2.5 CaCl2, 1 MgSO4, 1 KH2PO4, 10 dextrose, 24 NaHCO3, and 0.02 EDTA; it was bubbled with 21% O2-5% CO2-balance N2. The volume of the chamber was 10 ml, and a total of 100 ml of suffusion solution was recirculated at a rate of 40 ml/min to maintain temperature and pH. The solution was changed every 30 min. Intraluminal flow was established at a constant intravascular pressure (80 mmHg) by changing proximal and distal pressures controlled by two pressure-servo systems (Living Systems; Burlington, VT) to an equal degree, but in opposite directions, to keep the midpoint lumen pressure constant (17). The system was arranged to have mirror symmetry so that the axis of symmetry was located perpendicularly at the middle of the arteriolar segment. The pipettes used had similar dimensions and equivalent resistances to flow, as assessed by the changes in perfusion pressure in response to increments of flow by a Harvard perfusion pump. The flow rate was measured by a microflowmeter (FL-300, Omega; Stamford, CT), which can detect flow in a range from 0 to 100 µl/min. Internal diameter of arterioles was measured with an image-shearing monitor (model 908, Instrumentation for Physiology and Medicine; San Diego, CA) using a ×20 objective and a ×2.5 photo eyepiece, with a total magnification of ×385 on the screen of the monitor. Changes in diameter were recorded on a chart recorder (MC6625, Multicorder). Arterioles developed spontaneous tone (gradual decrease in diameter and finally reaching a stable diameter without the use of vasoconstrictors) at 80 mmHg of perfusion pressure in a no-flow condition. Changes in the diameter of arterioles in response to increases in perfusate flow were then studied. Perfusate flow was increased from 0 to 10 and from 10 to 20 µl/min. Each flow step was maintained for ~5 min to allow the vessels to reach a stable diameter. For the intraluminal administration of inhibitors, a small tubing was inserted into the inflow cannula, and only minimal space (~8 µl) was left from the end of the tubing to the tip of the cannula. While using pressure-servo control to maintain intraluminal pressure, inhibitors were administered into the lumen of the vessels at a rate of 2 µl/min.Flow- and agonist-induced dilations.
The role of microtubules in flow-induced dilation was assessed
according to the following protocol. After a control flow-diameter curve was obtained, nocodazole (5 × 109-5 × 106 M) or colchicine (5 × 107 M)
was added to the perfusion solution for 1-4 h. Then flow-induced dilations were assessed once more. Vasodilator responses to
acetylcholine (ACh; 108 M), sodium nitroprusside (SNP;
107 M), arachidonic acid (AA; 5 × 106
M), and prostaglandin E2 (PGE2;
108 M) were also examined before and after administration
of nocodazole or colchicine. At the conclusion of each experiment, the
suffusion solution was changed to Ca2+-free PSS containing
1 mM EGTA. Vessels were incubated for 10 min to reach their maximal
passive diameter at 80 mmHg of perfusion pressure, and the internal
diameter of arterioles was then measured. The passive diameter was used
to assess the active tone generated by the arterioles in response to
intravascular pressure and to normalize the response of arterioles.
Fluorescent microscopy.
For analysis of the appearance of the microtubular network within the
arteriolar endothelium in control and after nocodazole or colchicine
treatment, en face preparations of isolated arterioles of rat gracilis
muscle were made. Briefly, the arterioles were cannulated and
pressurized in a vessel chamber, as described Preparation of
isolated arterioles. After a 1-h equilibration period, the vessel
was perfused with PSS or PSS plus nocodazole (5 × 109-5 × 106 M) or colchicine
(5 × 107 M) at a rate of 2 µl/min for 1-4 h.
At the end of the perfusion period, freshly prepared 4%
paraformaldehyde was perfused intraluminally for 5 min. The vessel was
then taken off the cannulas and further fixed with 4% paraformaldehyde
for an additional 2 h at 4°C. After fixation, the blood vessels
were washed in PBS, cut longitudinally with microscissors under a
dissecting microscope, and made to adhere on a Vectabond (Vector
Laboratories; Burlingame, CA)-coated slide with the endothelium facing
up. The vessel strips were permeabilized with 0.2% Triton X-100 for
4 h and treated with 10% normal goat serum for 30 min at room
temperature. The vessel segments were then incubated with a mixture of
mouse monoclonal antibodies to 
-tubulin and 
-tubulin (1:200
dilution) overnight at 4°C. After several washes in PBS, the tissues
were incubated with Cy3-conjugated goat anti-mouse IgG (1:200 dilution)
for 1 h at room temperature. Reaction was completed by washing
with PBS several times and mounting the coverslips in Vectashield
(Vector Laboratories). Negative control experiments were
performed using the above steps except for the step using primary
antibodies. The specimens were visualized by confocal microscopy
(MRC1000, Bio-Rad; Hercules, CA).
Chemicals.
Cy3 was obtained from Jackson ImmunoResearch Laboratories (West Grove,
PA). All other drugs and chemicals were obtained from Sigma (St. Louis,
MO). Nocodazole and colchicine were dissolved in DMSO
(102 M). The final concentration of DMSO in the perfusion
solution was <0.05% and had no visible effects on arteriolar
diameter. Aliquots were stored in 
20°C. All other solutions and
drugs were prepared on the day of the experiment.
Data analysis and statistics. Data are presented as the means ± SE; n indicates the number of rats. Only one vessel was used from each rat in each experimental protocol. Both absolute and normalized data were evaluated. Flow-induced dilation was analyzed by using two-way ANOVA of repeated measures. After a significant effect (by nocodazole or colchicine) was found, Tukey's and/or Kramer's post hoc tests were performed to determine the significance between means. Statistical evaluation of changes in basal diameter and agonist-induced dilation was done by paired Student's t-test. Means were considered significantly different when the P value was <0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Arterioles of rat gracilis muscle developed spontaneous tone in response to a perfusion pressure of 80 mmHg and reached a mean diameter of 62.5 ± 2.2 µm. The passive diameter of these arterioles was 118.6 ± 3.9 µm (n = 24).
The role of microtubules in flow-induced dilation was assessed by
intraluminal administration of nocodazole in various concentrations. As
the original tracing in Fig. 1
(top) depicts, increases in flow from 0 to 20 µl/min in
control conditions elicited arteriolar dilation. In the
presence of 5 × 107 M nocodazole, flow-induced
dilations were abolished. Summary data of the effects of nocodazole on
flow-induced dilation are shown in Fig. 1 (bottom). The
basal diameter of arterioles and agonist-induced vasodilator responses,
including endothelium-dependent dilation to ACh (108 M)
or AA (5 × 106 M) and endothelium-independent
dilation to SNP (107 M) or PGE2
(108 M), were not affected by intraluminal administration
of 5 × 107 M nocodazole (Fig.
2). Intraluminal administration of
nocodazole at concentrations of 5 × 109 and 5 × 108 M did not affect flow-induced dilation (Fig.
3). In separate experiments, we found
that intraluminal incubation of 5 × 108 M
nocodazole for 4 h had no significant effect on flow-dependent dilations (Fig. 4). However, 5 × 106 M nocodazole caused a progressive decrease in
arteriolar diameters (64.7 ± 2.1 µm in control and 46.5 ± 2.9 µm after 1-h incubation with 5 × 106 M
nocodazole, n = 10, P < 0.05).
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The distribution of microtubules in the endothelium of gracilis muscle
arterioles was examined in en face preparations by immunostaining
against -tubulin and -tubulin. Disappearance of polymerized
tubulin was observed in 5 × 107 M
nocodazole-treated vessels (Fig.
5E) but was not observed in either control vessels (Fig. 5A) or vessels treated with
nocodazole at concentrations of 5 × 109 M (Fig.
5B) and 5 × 108 M (Fig. 5C)
for 1 h or 5 × 108 M for 4 h (Fig.
5D).
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Flow-induced dilation was also assessed before and after administration
of 5 × 107 M colchicine. The original record and
summary data shown in Fig. 6 indicate
that colchicine eliminated flow-induced dilation in arterioles of rat
gracilis muscle. Also, this inhibition of flow-induced dilation by
colchicine occurred concurrent with the disappearance of microtubular
structures in the endothelium (Fig. 5F). On the other hand,
as with nocodazole, vasodilator responses to ACh (108 M)
and SNP (107 M) were not affected by colchicine (Fig.
7).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study demonstrates that disruption of endothelial microtubules inhibits flow-induced dilation of skeletal muscle arterioles without effects on agonist-induced NO- and prostaglandin-dependent arteriolar dilation.
Increases in fluid shear stress were shown to elicit significant dilation of skeletal muscle arterioles in vivo (10, 15, 16) and in vitro (18, 19), implicating an important role for the shear stress-sensitive response in the local regulation of skeletal muscle blood flow. Shear stress-induced dilation in several vascular beds has been shown to be mediated by endothelial factors, primarily NO and prostaglandins (17-19). Previous studies of endothelial cells in culture utilized a cone plate system and increases in superfusate flow to increase shear stress above the cells (1, 5, 8, 14). These studies revealed several possible steps in the transduction of the shear stress signal, yet there are only few studies addressing the endothelial mechanotransduction in microvessels in which a vasomotor response can also be observed. In addition to second messengers (8, 14), the shape and structure of endothelial cells are also affected by shear stress (6, 7, 20, 21). Characteristic findings to exposure to shear stress include elongation of endothelial cells in the axis of the flow and rearrangement of microfilaments (29). These changes, however, develop over a significantly longer time scale (minutes and hours) than do vasomotor responses.
With the use of a cascade bioassay system, Hutcheson and Griffith (12) showed that increases of perfusate viscosity elicit the release of endothelium-derived relaxing factor from isolated rabbit aortic rings, which, however, was blocked by agents that disrupt endothelial F-actin filaments or the microtubular network. On the other hand, relaxation of the vessel to ACh or SNP was not affected. Thus there still remains the question as to whether an intact endothelial cytoskeleton is required for shear stress-induced dilation of microvessels, a rich source of vasoactive mediators and the most important determinants of peripheral resistance.
In a recent study, Platts et al. (25) also utilized
nocodazole and colchicine, aiming to study the effects of microtubule disruption on the pressure-induced tone of arteriolar smooth muscle. They administered these agents extraluminally at a concentration of 10 µM and found that vascular tone increased independent of the
endothelium. To study the effects of these agents directly on
endothelial cells, we administered them intraluminally at various concentrations (5 × 109-5 × 106 M). It has been shown previously that nocodazole,
similar to vinblastine, stabilizes microtubules at lower concentrations
and disassembles microtubules at higher concentrations
(13). Others (12) have also found that 500 nM
colchicine disrupted endothelial microtubules of cultured rabbit aortic
endothelial cells. In the present study, we found that nocodazole and
colchicine at a concentration of 5 × 107 M, while
inhibiting dilations in response to increases in perfusate flow, did
not change the myogenic tone of arterioles generated in response to 80 mmHg of intraluminal pressure nor did they affect agonist-induced
vasodilation. These results suggest that the microtubule-disrupting agents, when administered intraluminally at a relatively low
concentration, specifically target the endothelium rather than vascular
smooth muscle. Consistent with the results of Platts et al.
(25), we also found that intraluminal administration
of a higher concentration of nocodazole (5 × 106 M)
results in a significant increase in arteriolar tone, which could
result from disrupting microtubules in both the endothelium and smooth
muscle cells.
Previous studies showed that chronic changes in flow over endothelial
cells in culture results in the remodeling of endothelial cytoskeletal
fibers (7) and that the structure of cytoskeleton may be
important in the transduction of mechanical forces through endothelial
cells (6, 7). In this context, in mesenteric arteries of
homozygous vimentin-knockout mice (vimentin being the main structural
protein of intermediate filaments), Henrion et al. (11)
showed that flow-induced dilation is reduced compared with those of
wild-type control mice. Whether a change in tension development in or
an acute deformation of the elements of the cytoskeleton is involved in
the synthesis and/or release of endothelial factors eliciting
vasodilation in response to an increase in shear stress is not known.
Thus, in the present study, the role of microtubules in flow-induced
dilation of arterioles was assessed. In control conditions, step
increases in flow elicited substantial dilation of arterioles.
Intraluminal perfusion of nocodazole or colchicine, agents that block
microtubule polymerization (24), at a concentration of
5 × 107 M for 1 h disrupted endothelial
microtubules (Fig. 5, E and F) and abolished
flow-induced dilations (Figs. 3 and 6). In contrast, intraluminal
perfusion of nocodazole at lower concentrations, 5 × 109 or 5 × 108 M for 1 h or
5 × 108 M for 4 h [concentrations that are
believed to stabilize microtubules and result in mitotic arrest
(13)], did not disrupt endothelial microtubules (Fig. 5,
B, C, and D) nor did they affect
flow-induced dilation (Figs. 1 and 2). These results support our
hypothesis that the integrity of the endothelial cytoskeleton is
essential for the transduction of the shear stress signal. The
distribution and network structure of endothelial microtubules of
isolated skeletal muscle arterioles was comparable with those reported earlier with en face staining of porcine aortic endothelial cells (27). In the present study, dilator responses to ACh, SNP,
AA, and PGE2 were not significantly affected by nocodazole
or colchicine (Figs. 4 and 7), indicating that the endothelial signal
transduction mechanisms involved in response to changes in mechanical
forces are not the same as those responsible for receptor-induced
synthesis of endothelial factors (21, 23).
The present findings are consistent with some previous in vitro studies and extend them to arterioles of skeletal muscle. We speculate that a similar signal transduction cascade is responsible for shear stress-induced release of endothelial mediators, whether NO in pig coronary vessels (19), prostaglandins in the cremaster muscle (18), or both NO and prostaglandins in gracilis muscle arterioles (17) of rats. While we cannot exclude the possibility that disruption of the cytoskeleton may, in a direct or indirect manner, affect other endothelial structures and signaling molecules, it is likely that an alteration in cytoskeletal structure in response to a deformation of the endothelial cell membrane is one of the initial events in the transduction of the shear stress signal in all of the above-mentioned vessels. In contrast, in cultured human umbilical vein endothelial cells, it was reported that flow-induced NO release did not require an intact actin or microtubule network (14). The structure and function of the cytoskeleton of cultured endothelial cells, however, is likely to be different from those of native arteries and arterioles, which may be responsible for these disparate observations.
There are several other biochemical messengers that have been proposed to be involved in the transduction of the shear stress signal in endothelial cells leading to release of mediators. A role for the glycocalyx on the lumenal surface of the endothelium was suggested by Hecker et al. (10), whereas roles for Ca2+-sensitive K+ channels (1), tyrosine kinases (4), and G proteins (8) have also been proposed. In a recent study, Muller et al. (23) reported that integrin-matrix interactions at the abluminal side of endothelial cells are also essential in the signaling pathway of shear stress-induced vasodilation. The final common pathway of these mechanisms may be an increase in Ca2+ in endothelial cells (28), resulting in the stimulation of NO and prostaglandin synthesis. Indeed, previous studies have suggested that GTP- and cytoskeleton-dependent communication between endothelial Ca2+ stores is an important determinant of cellular function, which could modulate the availability of Ca2+ to be released (9). The complexity and perhaps the specificity of these processes is suggested by recent studies of Fleming et al. (3) questioning the obligatory role of an extended increase in intracellular Ca2+ concentration in shear stress-induced NO release, whereas Corson et al. (2) emphasized the importance of the phosphorylation of endothelial NO synthase in this process. Further extensive studies are needed not only to better characterize these pathways but also to elucidate the spatial and temporal relationships among them.
In summary, our study demonstrates for the first time that a functionally intact microtubular system is required for the endothelial signal transduction of shear stress in skeletal muscle arterioles by providing the structural basis for the transmission of this force leading to biochemical events and the synthesis of endothelial factors, which, in turn, elicit dilation and regulation of shear stress in microvessels.
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ACKNOWLEDGEMENTS |
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We thank Miriam Nunez and Dana Spencer for excellent secretarial assistance.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants PO1 HL-43023 and HL-46813.
Address for reprint requests and other correspondence: G. Kaley, Dept. of Physiology, New York Medical College, Valhalla, NY 10595 (E-mail: Gabor_Kaley{at}nymc.edu).
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. Section 1734 solely to indicate this fact.
Received 14 July 2000; accepted in final form 18 December 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Science
260:
1124-1127,
1993
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