© 2000 American Heart Association, Inc.
Integrative Physiology |
Impaired Conduction of Vasodilation Along Arterioles in Connexin40-Deficient Mice
From the Physiologisches Institut (C.d.W., F.R., S.-S.B., U.P.), Ludwig-Maximilians-Universität München, München, Germany; Institut für Genetik (S.K., O.K., K.W.), Abt. Molekulargenetik, Universität Bonn, Bonn, Germany.
Correspondence to Dr Cor de Wit, Physiologisches Institut, Ludwig-Maximilians-Universität, Schillerstr. 44, 80336 München, Germany. E-mail dewit{at}lrz.uni-muenchen.de
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Abstract |
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Abstract—Connexins have been hypothesized to play an important role in intercellular communication within the vascular wall and may provide a mechanistic explanation for conduction of vasomotor responses. To test this hypothesis, we studied the transmission of vasomotor responses in the intact skeletal muscle microcirculation of connexin40-deficient mice (Cx40-/-). Arterioles were locally stimulated with hyperpolarizing dilators (acetylcholine [ACh] as well as bradykinin [Bk]) or depolarizing K+ solution, and the resulting changes in diameter were measured using a videomicroscopy technique at the site of application and up to 1.32 mm upstream. Arterial pressure was elevated 25% in Cx40-/- mice (94±5 versus 75±4 mm Hg). Vessels selected for study had equivalent basal diameter and vasomotor tone in both genotypes of mice. Vasomotion was present in small arterioles of both genotypes, but its intensity was exaggerated in Cx40-/- mice. ACh and Bk induced dilation (33% and 53%, respectively, of maximal response) at the site of application that was of similar magnitude in both genotypes. These dilations were observed to spread upstream within <1 second without significant attenuation in Cx40+/+ mice. However, spreading was severely attenuated in Cx40-/- animals (11±4% versus 35±7% with ACh and 38±5% versus 60±7% with Bk in Cx40-/- and Cx40+/+, respectively; P<0.05). In contrast, conducted vasoconstrictions, induced by K+ solution decreased equally with distance in both genotypes. These results support a significant role for Cx40 in vascular intercellular communication. Our observations indicate that Cx40 is required for normal transmission of endothelium-dependent vasodilator responses and may underlie altered vasomotion patterns.
Key Words: hypertension • acetylcholine • bradykinin • endothelium • gap junctions
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Introduction |
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The regulation of blood flow in a wide dynamic range requires coordinated responses of resistance and feeding arteries. Such a coordination between vessels can be achieved by the vascular effects of shear stress1 exerted by the streaming blood or by conduction of vasomotor signals along cells of the vascular wall.2 Indeed, local application of certain vasoactive compounds, such as acetylcholine (ACh) or norepinephrine (NE) induced not only local dilation or constriction but also vasomotor responses several millimeters upstream and downstream.3 4 Vasomotor responses can also be conducted from capillaries to arterioles5 6 and may contribute to the matching of tissue demands and blood supply. This has been demonstrated in the following way: When single muscle fibers were stimulated to contract, arterioles upstream of capillaries supplying these fibers were observed to dilate.7
The high conduction velocity is consistent with electrotonic transmission of a signal along the vascular wall. In fact, locally induced hyperpolarizations and depolarizations have been demonstrated to be conducted several millimeters upstream in endothelial and vascular smooth muscle cells.8 The conduction of the electrical signal requires coupling of vascular cells by gap junctions that provide conduits of low electrical resistance between the cells.9 10 In vascular tissue, at least three different connexin (Cx) proteins (Cx37, Cx40, and Cx43) are expressed11 that form gap junctions. Cx40 seems to be the predominant connexin isoform in aortic endothelial cells,11 12 whereas in smooth muscle, Cx43 expression is abundant.11 Unfortunately, little information on the distribution pattern of connexins at the microcirculatory level is available.13
In the present study, we investigated the functional role of Cx40-containing gap junctions in the conduction of vasomotor signals, using mice deficient in this connexin protein.14 Hyperpolarizing endothelium-dependent vasodilators, depolarizing K+ solutions, or NE was applied locally as a short pulse, and the resulting conduction of vasomotor responses was studied in wild-type and in Cx40-deficient mice. Given that we hypothesized that a potential defect in vascular cell coupling could alter peripheral vascular resistance resulting in hypertension, we also investigated arterial pressure in these animals.
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Materials and Methods |
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Experimental Setup
Experiments were conducted in accordance with the German animal protection law. Cx40-deficient mice (Cx40-/-)14 and wild-type littermates (Cx40+/+) were anesthetized by droperidol (20 mg/kg), fentanyl (0.1 mg/kg), and midazolam (2 mg/kg IP), followed by continuous infusion (jugular vein). Arterial pressure was measured in the carotid artery, and heart rate was obtained from pressure pulse. The cremaster muscle was prepared as described15 and superfused with bicarbonate-buffered (pH 7.4, PO2
30 mm Hg; PCO2 38
mm Hg) salt solution ([in mmol/L] Na+
143, K+ 6, Ca2+ 2.5,
Mg2+ 1.2, Cl- 128,
HCO3- 25,
SO42- 1.2, and
H2PO4-
1.2). One or two arterioles were studied in each animal and observed
using a microscope equipped with a video camera. Images were displayed
on a video monitor and recorded on videotape for measurement of
luminal diameters (video dimension analyzer; IPM).
Experimental Protocols
After stabilization (30 minutes), sodium nitroprusside
(SNP, 10 µmol/L) followed by ACh (10 µmol/L) was
superfused. To study conduction of vascular responses, a micropipette
(tip 1 to 2 µm) was positioned in close proximity to the
arteriolar wall. ACh (10 mmol/L), bradykinin (1 mmol/L), NE
(1 mmol/L), or KCl or NaCl (3 mol/L) was applied by pressure
ejection (60 to 180 kPa, 100 to 600 ms) to obtain a response at the
site of stimulation. The same stimulation was then used, and responses
were studied at locations 0.33, 0.66, 0.99, and 1.32 mm upstream.
Stimulations with KCl were repeated in the presence of
phentolamine (0.1 µmol/L). Maximal diameter was measured
during combined superfusion of adenosine, SNP, and papaverine
(10 µmol/L each).
Immunohistochemistry
After anesthesia, the vasculature was flushed with
saline through the left ventricle and the tissue was fixed with
paraformaldehyde (2%). The cremaster muscle was
embedded in OCT (Tissue Tek) and frozen in isopentane (-160°C).
Sections (6 µm) were blocked with Tween (0.1%) and BSA (4%)
and were immunolabeled with rabbit anti-Cx4016 and goat
anti-factor VIII–related antigen (BIOTREND). Immunocomplexes were
visualized using Cy2-conjugated and Cy3-conjugated donkey IgG
(DIANOVA).
Statistics and Calculations
Vascular tone is expressed as a quotient of resting diameter
divided by maximal diameter. Diameter changes were normalized to the
maximal possible constriction or dilation: % of maximal
response=(DTr-DCo)/(DM-DCo)x100,
where DTr represents the diameter after
treatment and DCo is the control diameter.
DM represents the maximal observed change
in diameter (dilation or constriction). The "time to peak response"
(interval between stimulus application and attainment of peak diameter)
and the "response duration" (interval between stimulus and 50% of
recovery) were calculated. The latter was used to calculate the
integral of the dilation.
Comparisons within groups were performed using paired t tests and corrected according to Bonferroni. Data between groups were compared with ANOVA followed by post hoc analysis of the means or by Kruskal-Wallis test. Data are presented as mean±SEM. Differences were considered significant at a corrected error probability of P<0.05.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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Arteriolar Resting Tone and Dilations Induced by Superfusion of Vasomotor Stimuli
A total of 52 arterioles were studied in 28 mice. The mean maximal diameters of arterioles were not significantly different between genotypes (Cx40+/+: 39.3±2.3 µm; Cx40-/-: 37.9±2.1 µm). The vessels exhibited a varying degree of resting tone from 0.24 to 0.96 (mean: 0.63±0.03). In both genotypes, arteriolar resting tone was significantly higher in small (maximal diameter <35 µm) compared with large (maximal diameter >35 µm) vessels (Cx40+/+: small 0.52±0.06, large: 0.74±0.04, n=10 and 16, P<0.05; Cx40-/-: small: 0.50±0.07, large: 0.72±0.04, n=9 and 12, P<0.05). The addition of ACh (10 µmol/L) to the superfusion fluid induced nearly maximal dilation in Cx40+/+ mice, whereas in Cx40-/- animals, it was attenuated (Figure 1
). In contrast, dilations in response to
the nitric oxide donor SNP were not different (Figure 1).
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Local Stimulation With Endothelium-Dependent
Dilators
Local stimulation of the arterioles in wild-type mice with a short
pulse of ACh induced a dilation that reached within 3.4±0.5 seconds
(time to peak) a maximum of 35.6±4.1% at the stimulation site and
lasted for 21.0±5.0 seconds (response duration). Although maximal
dilation (32.8±5.6%) and time to the peak response (3.3±0.4 seconds)
were virtually identical at the local site in
Cx40-/- mice, the response duration was
significantly shortened (8.8±2.2 seconds, P<0.05 versus
Cx40+/+). The local dilation was rapidly
conducted upstream in both genotypes (Figure 2; the Table provides resting and maximal
diameters). In wild-type mice, the maximal amplitude did not decrease
up to 1.32 mm upstream (34.8±6.9%), and the time to peak value
was not different (4.1±0.7 seconds). However, with increasing
distance, the response became shorter (8.7±1.3 seconds,
P<0.05 versus local site). Although the local dilation on
ACh application was of virtually the same amplitude in
Cx40-/- mice, upstream dilations were
significantly attenuated compared with wild-type mice (Figure 2). The dilation 1.32 mm upstream was reduced to a maximum
amplitude of 11.2±4.3% in Cx40-/- mice
(P<0.05 versus local site). The response duration was only
3.5±1.3 seconds (P=0.07 versus local site) and, thus, like
the local response, significantly shorter than the response in
Cx40+/+ mice. When ACh was applied at a distance
of 0.2 mm from the vessel wall, no significant changes in diameter
were found (15.0±1.4 versus 16.5±1.9 µm, n=6).
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, n=10). B through E, Whereas
the amplitude of vasodilation at upstream sites (B: 0.33 mm; C:
0.66 mm; D: 0.99 mm; and E: 1.32 mm) remained virtually
unchanged in wild-type mice, it was severely attenuated in
Cx40-/- mice. Dilation is expressed as a percentage of
maximal response. The Table
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Bradykinin induced a local dilation of more than 50%, which was not
different in both genotypes. As was found with ACh, the
upstream dilation was not attenuated in wild-type mice, whereas it
decreased in amplitude with increasing distance in
Cx40-/- animals (Figure 3). Response durations were virtually
identical in both genotypes at all different sites studied
(Figure 3) as was the time to peak response (data not
shown).
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Local Application of High K+ Solution
Application of 3 mol/L K+ through the
micropipette induced a rapid constriction, which was also conducted
upstream. In contrast to endothelium-dependent
dilators, there was a monotonic decrease of the conducted response with
increasing distance in both genotypes (Figure 4). The maximal response decreased from
-39.1±4.5% and -39.6±5.4% to -10.2±4.2% and -13.3±2.8%
(Cx40+/+ and Cx40-/-,
respectively). There were also no significant differences in time to
peak response (data not shown), and duration of the response was not
different at the local site (5.1±0.4 seconds in both
genotypes). In contrast, duration of the responses was
significantly longer in Cx40-/- at the most
upstream sites (0.99 mm: 4.5±0.7 versus 2.3±0.7 seconds,
P<0.05; 1.32 mm: 4.2±0.8 versus 1.9±0.7 seconds).
Again, application of K+ solution 0.2 mm
apart from an arteriole did not induce significant changes in diameter
(36.8±2.0 versus 36.5±2.0 µm, n=9). If NaCl (3 mol/L) was
applied instead of KCl, diameters remained unaffected at the site of
application (38.7±3.7 versus 38.0±3.0 µm after 4 seconds, n=8)
as well as at upstream sites (data not shown).
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To study the role of NE release from perivascular nerves in the
conduction process, vessels were stimulated with
K+ solution before and after superfusion of the
-receptor antagonist phentolamine (0.1
µmol/L). The efficacy of the blockade was verified by the abrogation
of the constriction induced by superfusion of NE (0.1 µmol/L),
which amounted to -23.8±11.1% in the absence of the
antagonist. However, phentolamine did not affect
the constriction induced by K+ application at the
local (-41.5±8.0 versus -49.1±8.0%) or upstream sites (0.3
mm: -29.1±4.6 versus -33.7±3.7%; 0.66 mm: -13.1±2.4 versus
-16.6±3.3%, before and after blockade of -receptors,
respectively, n=7).
Local Application of NE
Local application of NE induced a strong constriction, which
reached within 8.2±1.4 seconds a maximum of -43.2±4.3% and lasted
for 15.1±2.9 seconds (n=9). Thus, these constrictions were similar to
those initiated by local KCl application (see Figure 4
).
Nevertheless, no significant constrictions were observed at upstream
sites. The maximal constriction at the nearest observed upstream site
(0.33 mm) amounted to -2.2±1.3% (P=0.09).
Immunostaining
To confirm the presence of Cx40 in wild-type mice in cremasteric
vessels, immunohistochemistry was performed on cryosectioned tissue.
Cx40 staining was revealed in cremasteric vessels (Figure 5B). The Cx40 antibodies colocalized with
antibodies directed against the endothelial marker
anti-factor VIII–related antigen (Figure 5C). Cx40 staining was
not detected in cremaster vessels from Cx40-/-
mice (Figures 5D through 5F).
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Arterial Pressure
The mean arterial pressure in wild-type mice (n=10
animals) remained throughout the experiment between 71 and 76
mm Hg, which is in a range reported by others for anesthetized
mice.17 In sharp contrast, the arterial
pressure in Cx40-/- animals (n=9) was
significantly elevated by 25% (Figure 6). Heart rate did not differ between
both genotypes (Figure 6).
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Conducted Responses Induced by ACh in Other Hypertensive
Mice
The conduction of endothelium-dependent
vasodilation was additionally studied in eNOS-deficient mice, which are
also characteristically hypertensive.18
Arterial pressure was 99±6 mm Hg in our experiments.
Application of ACh induced a dilation that amounted to 36.1±6.5% 5
seconds after stimulation. The dilation was rapidly conducted upstream.
Thus, 5 seconds after stimulation, a dilation of 34.9±4.7% at a
distance of 0.66 mm and 30.1±3.5% at 1.32 mm distance was
observed (n=7 vessels in 3 animals). These values were not
significantly different from normotensive Cx40+/+
mice (local: 37.4±4.6%, 0.66 mm: 28.4±3.9%, and 1.33 mm:
29.2±7.0%).
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Discussion |
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Our results show that Cx40 has a significant role in the propagation of vasodilations, initiated by local application of ACh or bradykinin. The propagation of vasodilations within the microcirculation in the mouse is likely due to vascular cell communication, which is substantially impaired in Cx40-deficient mice. Interestingly, the spread of vasoconstrictor responses initiated by a depolarizing K+ solution was not hampered. Because only the propagation of responses to endothelium-dependent stimuli was altered, we conclude that Cx40 has an essential role for efficient cell communication in the endothelial layer and/or in heterocellular coupling of endothelium and vascular smooth muscle.
The rapid conduction of the vasomotor responses along the arteriole
suggests that electrotonic spreading of locally initiated changes in
membrane potential may be the underlying mechanism. Indeed, ACh and
bradykinin have been shown to hyperpolarize
endothelial19 20 as well as vascular
smooth muscle cells by release of the
endothelium-derived hyperpolarizing factor
(EDHF)21 and/or nitric oxide.22 Electrotonic
conduction is characterized by a decrease of the change in membrane
potential with increasing distance. Accordingly, conducted diameter
changes decayed in hamster microvessels. From data obtained in vitro, a
length constant of 0.7 mm was calculated for the changes of
membrane potential,23 whereas length constants for
vasomotor responses were considerably higher (2
mm)24 25 but varied in different tissues.26
In the mouse cremasteric vessels, we did not find a decrease of the
vasomotor response up to our maximal observation distance of 1.32
mm (Figures 3 and 4), which suggests that a regenerative
mechanism might be involved. Therefore, we term the spreading of these
endothelium-dependent dilations "propagation" to
delimit these responses from passive conduction. The local release of
EDHF leading to hyperpolarization, which might have
contributed to the observed length constants, is less compromised
during neuroleptanalgesia compared with pentobarbital
narcosis,27 which was mostly used in
hamsters.24 Additionally, dissipation of conducted
vasomotor responses has been reported to be related to arteriolar
branching structure,23 28 which might vary between
species.
Local depolarization by elevation of the K+
concentration initiated upstream vasoconstrictions that were not due to
the release of adrenergic neurotransmitters released from perivascular
nerves because the effective blockade of -adrenergic receptors did
not affect the responses. Moreover, changes in osmolarity could not
account for the observed phenomenon in view of the fact that similar
application of NaCl, exhibiting identical osmolarity, did not induce
significant changes in diameter. Thus, it is likely that smooth muscle
depolarization initiated the responses. The incompetence of locally
applied NE to induce conducted responses might relate to only minimal
depolarization induced by this substance. It has to be kept in mind
that endothelial depolarization might have contributed
to the K+-induced constriction, because
endothelial cell depolarization, which should occur
during K+ application, would decrease the driving
force for endothelial Ca2+
influx, and release of endothelial vasodilators, as a
result, decreases. However, because of the observed time course,
depolarization of smooth muscle and subsequent constriction are most
likely the underlying mechanisms. Interestingly, constrictions decayed
with increasing distance in marked contrast to
endothelium-dependent dilations. This divergence of
length constants suggests that the changes in membrane potential
propagate along different pathways, presumably
endothelial and vascular smooth muscle cells. It is not
clear to what extent both cell types are coupled by heterocellular gap
junction channels. In vitro data support the notion that heterocellular
coupling exists.29 30 31 In contrast, from measurements
obtained in the hamster microcirculation in vivo, it has been proposed
that each cell layer, ie, the endothelium and the
smooth muscle, forms a separate electrical pathway.8 32 33
From our experiments, conclusions about the pathways used cannot be
readily deduced. However, our observation of different length constants
for endothelium-dependent dilators and
K+ solution would be consistent with
separate electrical pathways.
Most importantly, upstream dilations in response to local application
of endothelium-dependent dilators (ACh, bradykinin)
were diminished in Cx40-deficient vessels. This attenuation is not
related to the hypertension found in these animals because
eNOS-deficient mice, which are characteristically
hypertensive,18 did not show such an attenuation. In
marked contrast to endothelium-dependent dilations, the
conduction of the depolarization-induced constrictions was not altered.
This divergent effect of Cx40 channel expression can be explained in
two ways. First, Cx40-containing gap junction channels may have a
significant role in endothelial cell coupling but not
in the communication of smooth muscle cells. Second, such gap junctions
channels may be critical in heterocellular coupling of
endothelium and vascular smooth muscle. Heterocellular
coupling has been described to play a central role in
endothelium-dependent relaxations.31 The
impairment of propagation of endothelium-dependent
dilations fits with our observations on the expression of connexins in
vascular tissue. We found costaining of Cx40 and of the
endothelial marker von Willebrand factor in
cremasteric microvessels of wild-type mice (Figure 5), which
indicates that mostly endothelial cells express this
protein. Similarly, in large rat arteries (aorta), Cx40 is expressed
most abundantly in endothelium and less frequently in
smooth muscle cells.11 12 However, Cx40 and Cx43 were
found in endothelial as well as vascular smooth muscle
cells in the cheek pouch microcirculation of hamsters.13
The exact localization of these connexins in the microcirculation,
which may help to decide between the proposed hypotheses, ie,
homocellular and/or heterocellular coupling, remains unclear. Our data,
however, demonstrate for the first time a functional role of Cx40 in
the microcirculation, given that its absence severely impairs
propagation of endothelium-dependent vasodilator
signals along the arteriole. However, even in the absence of Cx40, a
remaining dilation was found at upstream sites. This points to a role
of gap junction channels formed by other connexins that mediate the
remaining propagation along endothelial or smooth
muscle cells or between these cell types.
Surprisingly, the Cx40-deficient mice were hypertensive as judged by anesthetized blood pressure values. In the absence of any modulation of the level of anesthesia attributable to the Cx40-deficient phenotype, this indicates a role of vascular Cx40 in the control of blood pressure. Currently, we do not know which mechanisms are involved. However, our data yield some clues. First, the endothelium-dependent dilation in response to ACh was impaired as derived from superfusion experiments, which may be explained by a reduced responsiveness to ACh in partially uncoupled cells. It has been shown in the lung microcirculation that part of the intracellular Ca2+ increase upon ACh stimulation was due to an influence of neighboring cells.34 Second, the lack of coordination between downstream and upstream vessels as demonstrated may increase peripheral resistance. Third, we observed in 3 of 10 Cx40-deficient mice, a spontaneous and quite irregular vasomotion that did not occur in wild-type animals. The arterioles constricted completely over a short length for several seconds, giving the impression of local spasms and leading to complete flow cessation. These constrictions occurred repetitively and, if observed once, could be repeatedly identified along the vessel. These phenomena, which may occur also in other organs, could result in increased vascular resistance as well.
To our knowledge, the data in the present study provide the first experimental proof for a functional role of Cx40 in intercellular signaling underlying propagated vasodilation and in control of blood pressure. Most likely, other connexins also contribute to these effects. It will be challenging to dissect the interactions and complementary functions of different connexin proteins in the molecular physiology of the vessel wall using other targeted mouse mutants.
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Acknowledgments |
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This study was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 553, project B2) to U.P. and through SFB 284, project C1, the Biomed program of the European Union and the Fonds der Chemischen Industrie to K.W. The authors thank Dr Otto Traub (Institut für Genetik, Bonn, Germany), who provided the Cx40 antibodies, and Dr Axel Goedecke (Zentrum für Physiologie, Düsseldorf, Germany) for kindly supplying the eNOS-deficient mice.
Received December 17, 1999; accepted January 14, 2000.
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