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Circulation Research. 2000;86:649-655

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(Circulation Research. 2000;86:649.)
© 2000 American Heart Association, Inc.


Integrative Physiology

Impaired Conduction of Vasodilation Along Arterioles in Connexin40-Deficient Mice

Cor de Wit, Frederik Roos, Steffen-Sebastian Bolz, Susanne Kirchhoff, Olaf Krüger, Klaus Willecke, Ulrich Pohl

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


*    Abstract
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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


*    Introduction
up arrowTop
up arrowAbstract
*Introduction
down arrowMaterials and Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
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.


*    Materials and Methods
up arrowTop
up arrowAbstract
up arrowIntroduction
*Materials and Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
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 {approx}30 mm Hg; PCO2 {approx}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.


*    Results
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up arrowMaterials and Methods
*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 1Down). In contrast, dilations in response to the nitric oxide donor SNP were not different (Figure 1Down).



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Figure 1. Dilator response to stimulation by superfusion with ACh (10 µmol/L, left) or the nitric oxide donor SNP (10 µmol/L, right). In wild-type mice (n=11 arterioles, Cx40+/+, open bars), ACh induced a near maximal arteriolar dilation, whereas the dilation was attenuated in Cx40-/- mice (n=11 arterioles, hatched bars). In contrast, dilations induced by SNP were not different between genotypes. Dilation is expressed as a percentage of maximal response. *Significant differences between these groups (P<0.05).

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 2Down; the TableDown 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 2Down). 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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Figure 2. Time courses of responses to local pulse-pressure application of ACh via a micropipette as observed locally and at increasing distances upstream. A, Stimulation with ACh (10 mmol/L, 200- to 400-ms pulse of 80 to 120 kPa) induced a local dilation of similar magnitude in Cx40-/- (•, n=8 arterioles) and wild-type mice (Cx40+/+, {circ}, 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 TableUp provides resting and maximal diameters. *Significant differences of the area under the curve as calculated from dilation and response duration between genotypes (Kruskal-Wallis test). Arrow denotes time of ACh application.


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Table 1. Resting and Maximal Diameters of Arterioles Locally Stimulated With ACh, Bradykinin, or K+ Solution

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 3Down). Response durations were virtually identical in both genotypes at all different sites studied (Figure 3Down) as was the time to peak response (data not shown).



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Figure 3. Maximal amplitude (top) and duration (bottom) of dilations initiated by local application of bradykinin (1 mmol/L, 300- to 600-ms pulse of 70 to 140 kPa) in Cx40+/+ ({circ}) and Cx40-/- (•) as a function of distance from the stimulation site. In arterioles deficient in Cx40 protein, amplitude diminished with increasing distance. Dilation is expressed as a percentage of maximal response. See TableUp for resting and maximal diameters. *Significant differences between genotypes. Values were measured in 13 arterioles in mice of each genotype.

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 4Down). 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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Figure 4. Time courses of constrictions induced by local application of K+ solution (3 mol/L, 40- to 300-ms pulse of 80 to 140 kPa) in Cx40+/+ ({circ}) and Cx40-/- (•). In both genotypes, strong local vasoconstriction was observed (A), which propagated with monotonically decreasing amplitude to upstream sites (B: 0.33 mm; C: 0.66 mm; D: 0.99 mm; and E: 1.32 mm). Constriction is expressed as a percentage of maximal response. See TableUp for resting and maximal diameters. Data were obtained in 14 arterioles in each group of mice. The calculated integrals from constriction and response duration were not significantly different between genotypes at any site observed (Kruskal-Wallis test).

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 {alpha}-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 {alpha}-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 4Up). 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 5BDown). The Cx40 antibodies colocalized with antibodies directed against the endothelial marker anti-factor VIII–related antigen (Figure 5CDown). Cx40 staining was not detected in cremaster vessels from Cx40-/- mice (Figures 5DDown through 5F).



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Figure 5. Immunofluorescence analysis of cryostat sections of cremaster muscle of wild-type (A through C) and Cx40-/- (D through F) mice. Phase-contrast micrographs of sections of the cremaster muscle (A and D). These same sections stained with antibodies to Cx40 (B and E) and with antibodies to factor VIII–related antigen (C and F). Bar=15 µm.

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 {approx}25% (Figure 6Down). Heart rate did not differ between both genotypes (Figure 6Down).



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Figure 6. Arterial pressure (top) in anesthetized wild-type mice ({circ}) was in a range between 71 and 77 mm Hg over the complete experimental period. In contrast, the arterial pressure in Cx40-deficient animals (•) was elevated by {approx}25%. Heart rate (bottom) was not different between genotypes. Data were acquired in 10 (Cx40+/+) and 9 animals (Cx40-/-). *Significant differences.

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%).


*    Discussion
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up arrowAbstract
up arrowIntroduction
up arrowMaterials and Methods
up arrowResults
*Discussion
down arrowReferences
 
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 ({approx}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 3Up and 4Up), 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 {alpha}-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 5Up), 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.


*    Acknowledgments
 
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.


*    References
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMaterials and Methods
up arrowResults
up arrowDiscussion
*References
 
1. de Wit C, Schäfer C, von Bismarck P, Bolz SS, Pohl U. Elevation of plasma viscosity induces sustained NO-mediated dilation in the hamster cremaster microcirculation in vivo. Pflügers Arch. 1997;434:354–361.

2. Christ GJ, Spray DC, el Sabban M, Moore LK, Brink PR. Gap junctions in vascular tissues: evaluating the role of intercellular communication in the modulation of vasomotor tone. Circ Res. 1996;79:631–646.[Abstract/Free Full Text]

3. Segal SS, Duling BR. Flow control among microvessels coordinated by intercellular conduction. Science. 1986;234:868–870.[Abstract/Free Full Text]

4. Rivers RJ. Cumulative conducted vasodilation within a single arteriole and the maximum conducted response. Am J Physiol. 1997;273:H310–H316.[Abstract/Free Full Text]

5. Song H, Tyml K. Evidence for sensing and integration of biological signals by the capillary network. Am J Physiol. 1993;265:H1235–H1242.[Abstract/Free Full Text]

6. Welsh DG, Segal SS. Coactivation of resistance vessels and muscle fibers with acetylcholine release from motor nerves. Am J Physiol. 1997;273:H156–H163.[Abstract/Free Full Text]

7. Berg BR, Cohen KD, Sarelius IH. Direct coupling between blood flow and metabolism at the capillary level in striated muscle. Am J Physiol. 1997;272:H2693–H2700.[Abstract/Free Full Text]

8. Welsh DG, Segal SS. Endothelial and smooth muscle cell conduction in arterioles controlling blood flow. Am J Physiol. 1998;274:H178–H186.[Abstract/Free Full Text]

9. Goodenough DA, Goliger JA, Paul DL. Connexins, connexons, and intercellular communication. Annu Rev Biochem. 1996;65:475–502.[Medline] [Order article via Infotrieve]

10. Kumar NM, Gilula NB. The gap junction communication channel. Cell. 1996;84:381–388.[Medline] [Order article via Infotrieve]

11. Yeh HI, Rothery S, Dupont E, Coppen SR, Severs NJ. Individual gap junction plaques contain multiple connexins in arterial endothelium. Circ Res. 1998;83:1248–1263.[Abstract/Free Full Text]

12. Gabriels JE, Paul DL. Connexin43 is highly localized to sites of disturbed flow in rat aortic endothelium but connexin37 and connexin40 are more uniformly distributed. Circ Res. 1998;83:636–643.[Abstract/Free Full Text]

13. Little TL, Beyer EC, Duling BR. Connexin43 and connexin40 gap junctional proteins are present in arteriolar smooth muscle and endothelium in vivo. Am J Physiol. 1995;268:H729–H739.[Abstract/Free Full Text]

14. Kirchhoff S, Nelles E, Hagendorff A, Krüger O, Traub O, Willecke K. Reduced cardiac conduction velocity and predisposition to arrhythmias in connexin40-deficient mice. Curr Biol. 1998;8:299–302.[Medline] [Order article via Infotrieve]

15. de Wit C, von Bismarck P, Pohl U. Mediator role of prostaglandins in acetylcholine-induced vasodilation and control of resting vascular diameter in the hamster cremaster microcirculation in vivo. J Vasc Res. 1993;30:272–278.[Medline] [Order article via Infotrieve]

16. Traub O, Eckert R, Lichtenberg-Frate H, Elfgang C, Bastide B, Scheidtmann KH, Hülser DF, Willecke K. Immunochemical and electrophysiological characterization of murine connexin40 and -43 in mouse tissues and transfected human cells. Eur J Cell Biol. 1994;64:101–112.[Medline] [Order article via Infotrieve]

17. Barbee RW, Perry BD, Re RN, Murgo JP. Microsphere and dilution techniques for the determination of blood flows and volumes in conscious mice. Am J Physiol. 1992;263:R728–R733.[Abstract/Free Full Text]

18. Huang PL, Huang ZH, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995;377:239–242.[Medline] [Order article via Infotrieve]

19. Lückhoff A, Busse R. Calcium influx into endothelial cells and formation of endothelium-derived relaxing factor is controlled by the membrane potential. Pflügers Arch. 1990;416:305–311.

20. Chen GF, Cheung DW. Characterization of acetylcholine-induced membrane hyperpolarization in endothelial cells. Circ Res. 1992;70:257–263.[Abstract/Free Full Text]

21. Popp R, Bauersachs J, Hecker M, Fleming I, Busse R. A transferable, ß-naphthoflavone-inducible, hyperpolarizing factor is synthesized by native and cultured porcine coronary endothelial cells. J Physiol (Lond). 1996;497:699–709.[Abstract/Free Full Text]

22. Cohen RA, Plane F, Najibi S, Huk I, Malinski T, Garland CJ. Nitric oxide is the mediator of both endothelium-dependent relaxation and hyperpo-larization of the rabbit carotid artery. Proc Natl Acad Sci U S A. 1997;94:4193–4198.[Abstract/Free Full Text]

23. Segal SS, Neild TO. Conducted depolarization in arteriole networks of the guinea-pig small intestine: effect of branching on signal dissipation. J Physiol (Lond). 1996;496:229–244.[Abstract/Free Full Text]

24. Segal SS, Damon DN, Duling BR. Propagation of vasomotor responses coordinates arteriolar resistances. Am J Physiol. 1989;256:H832–H837.[Abstract/Free Full Text]

25. Xia J, Duling BR. Electromechanical coupling and the conducted vasomotor response. Am J Physiol. 1995;269:H2022–H2030.[Abstract/Free Full Text]

26. Steinhausen M, Endlich K, Nobiling R, Parekh N, Schütt F. Electrically induced vasomotor responses and their propagation in rat renal vessels in vivo. J Physiol (Lond). 1997;505:493–501.[Abstract/Free Full Text]

27. de Wit C, Esser N, Lehr HA, Bolz SS, Pohl U. Pentobarbital sensitive EDHF comediates ACh-induced arteriolar dilation in the hamster microcirculation. Am J Physiol. 1999;276:H1527–H1534.[Abstract/Free Full Text]

28. Segal SS, Welsh DG, Kurjiaka DT. Spread of vasodilatation and vasoconstriction along feed arteries and arterioles of hamster skeletal muscle. J Physiol (Lond). 1999;516:283–291.[Abstract/Free Full Text]

29. Beny JL. Electrical coupling between smooth muscle cells and endothelial cells in pig coronary arteries. Pflügers Arch. 1997;433:364–367.

30. Dora KA, Doyle MP, Duling BR. Elevation of intracellular calcium in smooth muscle causes endothelial cell generation of NO in arterioles. Proc Natl Acad Sci U S A. 1997;94:6529–6534.[Abstract/Free Full Text]

31. Chaytor AT, Evans WH, Griffith TM. Central role of heterocellular gap junctional communication in endothelium-dependent relaxations of rabbit arteries. J Physiol (Lond). 1998;508:561–573.[Abstract/Free Full Text]

32. Beny JL. Endothelial and smooth muscle cells hyperpolarized by bradykinin are not dye coupled. Am J Physiol. 1990;258:H836–H841.[Abstract/Free Full Text]

33. Segal SS, Beny JL. Intracellular recording and dye transfer in arterioles during blood flow control. Am J Physiol. 1992;263:H1–H7.[Abstract/Free Full Text]

34. Ying XY, Minamiya Y, Fu CZ, Bhattacharya J. Ca2+ waves in lung capillary endothelium. Circ Res. 1996;79:898–908.[Abstract/Free Full Text]




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Home page
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Home page
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J Appl Physiol, September 1, 2004; 97(3): 1152 - 1158.
[Abstract] [Full Text] [PDF]


Home page
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Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H216 - H224.
[Abstract] [Full Text] [PDF]


Home page
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Circ. Res., June 11, 2004; 94(11): 1401 - 1402.
[Full Text] [PDF]


Home page
Circ. Res.Home page
J. Christiansen, J. D. Dyck, B. G. Elyas, M. Lilley, J. S. Bamforth, M. Hicks, K. A. Sprysak, R. Tomaszewski, S. M. Haase, L. M. Vicen-Wyhony, et al.
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Circ. Res., June 11, 2004; 94(11): 1429 - 1435.
[Abstract] [Full Text] [PDF]


Home page
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Physiology, June 1, 2004; 19(3): 148 - 153.
[Abstract] [Full Text] [PDF]


Home page
J. Physiol.Home page
H. Takano, K. A. Dora, M. M. Spitaler, and C. J. Garland
Spreading dilatation in rat mesenteric arteries associated with calcium-independent endothelial cell hyperpolarization
J. Physiol., May 1, 2004; 556(3): 887 - 903.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
X. Lin and R. D. Veenstra
Action potential modulation of connexin40 gap junctional conductance
Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1726 - H1735.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
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Cardiovasc Res, May 1, 2004; 62(2): 287 - 298.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
J.-A. Haefliger, P. Nicod, and P. Meda
Contribution of connexins to the function of the vascular wall
Cardiovasc Res, May 1, 2004; 62(2): 345 - 356.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
S. L. Sandow, R. Looft-Wilson, B. Doran, T.H. Grayson, S. S. Segal, and C. E. Hill
Expression of homocellular and heterocellular gap junctions in hamster arterioles and feed arteries
Cardiovasc Res, December 1, 2003; 60(3): 643 - 653.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
A. Hoffmann, T. Gloe, U. Pohl, and S. Zahler
Nitric oxide enhances de novo formation of endothelial gap junctions
Cardiovasc Res, November 1, 2003; 60(2): 421 - 430.
[Abstract] [Full Text] [PDF]


Home page
Physiol. Rev.Home page
J. C. SAEZ, V. M. BERTHOUD, M. C. BRANES, A. D. MARTINEZ, and E. C. BEYER
Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions
Physiol Rev, October 1, 2003; 83(4): 1359 - 1400.
[Abstract] [Full Text] [PDF]


Home page
Arterioscler. Thromb. Vasc. Bio.Home page
H.-I Yeh, C.-S. Lu, Y.-J. Wu, C.-C. Chen, R.-C. Hong, Y.-S. Ko, M.-S. Shiao, N. J. Severs, and C.-H. Tsai
Reduced Expression of Endothelial Connexin37 and Connexin40 in Hyperlipidemic Mice: Recovery of Connexin37 After 7-Day Simvastatin Treatment
Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1391 - 1397.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
I. Fleming
Bobbing Along on the Crest of a Wave: NO Ascends Hamster Cheek Pouch Arterioles
Circ. Res., July 11, 2003; 93(1): 9 - 11.
[Full Text] [PDF]


Home page
J. Cell Sci.Home page
A. M. Simon and A. R. McWhorter
Decreased intercellular dye-transfer and downregulation of non-ablated connexins in aortic endothelium deficient in connexin37 or connexin40
J. Cell Sci., June 1, 2003; 116(11): 2223 - 2236.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2204 - H2212.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1721 - H1728.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
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Central Role of Connexin40 in the Propagation of Electrically Activated Vasodilation in Mouse Cremasteric Arterioles In Vivo
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Home page
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Lack of vascular connexin 40 is associated with hypertension and irregular arteriolar vasomotion
Physiol Genomics, April 16, 2003; 13(2): 169 - 177.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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Am J Physiol Lung Cell Mol Physiol, November 1, 2002; 283(5): L875 - L893.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H996 - H1004.
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Home page
Arterioscler. Thromb. Vasc. Bio.Home page
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Altered Pattern of Vascular Connexin Expression in Atherosclerotic Plaques
Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 225 - 230.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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Effects of age, gender, and blood pressure on myogenic responses of mesenteric arteries from C57BL/6 mice
Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H380 - H388.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
A. R. Pries, B. Reglin, and T. W. Secomb
Structural adaptation of microvascular networks: functional roles of adaptive responses
Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1015 - H1025.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
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Lipopolysaccharide reduces intercellular coupling in vitro and arteriolar conducted response in vivo
Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1397 - H1406.
[Abstract] [Full Text] [PDF]


Home page
J. Physiol.Home page
Y. Yamamoto, M. F Klemm, F. R Edwards, and H. Suzuki
Intercellular electrical communication among smooth muscle and endothelial cells in guinea-pig mesenteric arterioles
J. Physiol., August 15, 2001; 535(1): 181 - 195.
[Abstract] [Full Text] [PDF]


Home page
Proc. Natl. Acad. Sci. USAHome page
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Endothelial cell-specific knockout of connexin 43 causes hypotension and bradycardia in mice
PNAS, July 24, 2001; (2001) 171305298.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Heart Circ. Physiol.Home page
S. Shigematsu, S. Ishida, D. C. Gute, and R. J. Korthuis
Postischemic anti-inflammatory effects of bradykinin preconditioning
Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H441 - H454.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
H. S. Tamaddon, D. Vaidya, A. M. Simon, D. L. Paul, J. Jalife, and G. E. Morley
High-Resolution Optical Mapping of the Right Bundle Branch in Connexin40 Knockout Mice Reveals Slow Conduction in the Specialized Conduction System
Circ. Res., November 10, 2000; 87(10): 929 - 936.
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Proc. Natl. Acad. Sci. USAHome page
Y. Liao, K. H. Day, D. N. Damon, and B. R. Duling
Endothelial cell-specific knockout of connexin 43 causes hypotension and bradycardia in mice
PNAS, August 14, 2001; 98(17): 9989 - 9994.
[Abstract] [Full Text] [PDF]


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