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Am J Physiol Heart Circ Physiol 295:2001-2007, 2008. First published Sep 12, 2008;
doi:10.1152/ajpheart.00063.2008
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Am J Physiol Heart Circ Physiol 295: H2001–H2007, 2008.
First published September 12, 2008; doi:10.1152/ajpheart.00063.2008.
Figueroa XF, Duling BR. Dissection of two Cx37-independent brane potential via gap junctional connection between adjacent
conducted vasodilator mechanisms by deletion of Cx40: electro- cells (17, 34). Both dilator and constrictor signals propagate
tonic versus regenerative conduction. Am J Physiol Heart Circ electrotonically, but, in addition, endothelium-dependent vaso-
Physiol 295: H2001–H2007, 2008. First published September 12, dilations have been observed to propagate along the entire
2008; doi:10.1152/ajpheart.00063.2008.—Conduction of changes in
vessel without decay, suggesting the activation of a regenera-
diameter plays an important role in the coordination of peripheral
vascular resistance and, thereby, in the control of arterial blood tive mechanism (6, 7, 10, 15, 33). The molecular basis for the
http://www.ajpheart.org 0363-6135/08 $8.00 Copyright © 2008 the American Physiological Society H2001
H2002 Cx40-DEPENDENT REGENERATIVE VASODILATION
Table 1. Characteristics of the mouse cremaster appropriate. At the end of the experiment, animals were euthanized by
arterioles studied an anesthetic overdose.
Vessel diameters. The cremaster muscle was transilluminated, and
Maximum Resting Resting the microscope image was projected to a video camera (series 65,
n Diameter, m Diameter, m Tone, % Dage-MTI) whose output was displayed on a monitor (model
Wild-type mice 23 38.8⫾1.6 21.0⫾1.6 46.8⫾2.6 HR1000, Dage-MTI). Inner diameters of the arterioles were continu-
Cx40 knockout mice 19 30.4⫾1.4* 16.8⫾0.8 44.7⫾1.6 ously measured using Diamtrak software (15, 47).
Cx37 knockout mice 12 35.4⫾2.5 16.2⫾1.7 55.3⫾1.9 Arterioles of the second and third order were stimulated focally
with a pressure-pulse ejection from a micropipette (inner diameter:
Values are means ⫾ SE; n, no. of mice. Cx40, connexin40; Cx37, con-
3– 4 m) of either the KATP channel opener pinacidil (100 M) or
nexin37. *P ⬍ 0.05 vs. wild-type mice by one-way ANOVA plus the
Newman-Keuls post hoc test. ACh (10 M). The duration of the stimulation period was set to
induce a local vasodilation of ⬃50% (pinacidil: 500 –700 ms and
ACh: 300 ms). In one group of experiments, the length of the pulse of
two agonists is quite different. In contrast to pinacidil, the ACh was extended to 700 ms to elicit maximal vasodilation at the
vasodilation evoked by ACh does not decay along the arteriolar stimulation site. Changes in diameter were measured first at the
length, and Cx40 seems to be critical only for the conduction stimulation site (local) and then at locations 500, 1,000, and 2,000 m
of the nondecremental component of the ACh-activated vaso- upstream in four separate stimuli. To allow the recovery of the
dilator signal. vasodilator response and the stabilization of the control diameter, the
time interval between stimulations was set at 3 min for ACh and 5 min
Fig. 1. Time course of local and conducted vasodilation induced by pinacidil in wild-type mice. A short segment of the cremasteric arteriole was stimulated with
a pressure-pulse ejection via micropipette of the ATP-sensitive K⫹ (KATP) channel opener pinacidil, and the resultant vasodilator responses were observed at
the stimulation pipette site (local) and at locations 500, 1,000, and 2,000 m upstream. Note that the changes in diameter decayed rapidly along the vessel length.
Arrows indicate the time at which the stimulus was applied.
Fig. 6. Systolic blood pressure (SBP) of WT, Cx37⫺/⫺, and Cx40⫺/⫺ mice.
Fig. 4. Comparison of the peak response induced by pinacidil with that Deletion of Cx37 did not alter the arterial blood pressure, but elimination of
initiated by ACh in WT and Cx40⫺/⫺ mice. Maximal vasodilator responses of Cx40 resulted in marked hypertension. Numbers inside the bars indicate n
values. *P ⬍ 0.05 vs. WT or Cx37⫺/⫺ mice by one-way ANOVA plus the
Fig. 5. Time course of the conduction of maximal vasodilation induced by ACh in WT and Cx40⫺/⫺ mice. ACh was applied as described in Fig. 3, but
the duration of the pressure pulse was increased to 700 ms to stimulate maximal vasodilation in the segment of the arteriole just underneath the micropipette. The
vasodilator response was observed at the stimulation site (local) and at locations at 500, 1,000, and 2,000 m upstream. Arrows indicate the time at which the
stimulus was applied. *P ⬍ 0.05 vs. WT mice by one-way ANOVA plus the Newman-Keuls post hoc test.
erative vasodilator mechanism as has been recently described vasodilator response propagated beyond 500 m from the local
for the electrically induced conducted vasodilation (12). site (41). It is important to note that the vasodilation induced by
The response to ACh might be conducted by either the NO is not conducted along the length of arterioles (9, 20), and
endothelium or smooth muscle in arterioles (1, 3). However, the hyperpolarization of endothelial cells is not coupled to an
the regenerative propagation of the vasodilation induced by increase in intracellular Ca2⫹ in intact vessels (32, 40), as was
ACh depended on the expression of Cx40 (Figs. 3 and 4), and, proposed by Budel et al. (3) to explain the activation of
in cremasteric arterioles, Cx40 is only expressed in the endo- endothelial NO synthase (eNOS) at the conducted sites. In
thelium (7, 15), which we confirmed in the present work (Fig. addition, as mentioned above, focal stimulation with depolar-
7). Interestingly, deletion of Cx40 converted the nondecremen- izing pulses of current activates a nondecremental conducted
tal response activated by ACh into a rapidly decaying vasodi- vasodilator response of similar characteristics to those initiated
lator signal (Figs. 3 and 4). In addition, the longitudinal by ACh (15). Interestingly, the conducted response induced by
reduction of the vasodilation elicited by ACh in Cx40⫺/⫺ mice electrical stimulation of mouse cremaster arterioles is also
was similar to that observed with pinacidil stimulation (Fig. 4). coupled to NO production and is associated to the activation of
Therefore, these results suggest that ablation of Cx40 selec- voltage-dependent Na⫹ and Ca2⫹ channels in endothelial cells
tively disrupted the regenerative propagation of a vasodilator (12). Therefore, these data are consistent with the activation of
signal via endothelial cells but without affecting the electro- a voltage-dependent regenerative vasodilator signal by ACh
tonic component of the conducted response triggered by ACh, that is, in turn, coupled to eNOS activation and endothelial cell
which may be mediated by others Cxs expressed either in the hyperpolarization.