Cardiovascular Research 2003 60(3):457-459; doi:10.1016/j.cardiores.2003.10.005
© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Shear stress and intermediate-conductance calcium-activated potassium channels
Ed van Bavel*
Department of Medical Physics, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands
*Tel.: +31-20-5665203; fax: +31-20-6917233. Email address: e.vanbavel{at}amc.uva.nl
Received 29 September 2003; accepted 6 October 2003
See article by Brakemeier et al. [4] (pages 488–496) in this issue.
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1. Introduction
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Vascular endothelial cells (EC) are continuously exposed to
shear stress associated with the flowing blood. Over the years,
it has become clear that such shear exerts a multitude of effects
on endothelial biology and vascular function and structure,
ranging in time span from seconds to months. On the scale of
seconds, shear-dependent vasodilation has been demonstrated
in many experimental settings. In the course of months, shear
stress is believed to shape the vascular bed through remodeling
[1]. Thus, shear stress sensing provides a mechanistic base
for the notion of Murray in 1926 that vascular diameter should
be proportional to the cube of the carried flow in order to
minimize the costs of maintaining a circulation
[2]. Steady
laminar shear is atheroprotective while low shear levels and
temporal or spatial variation of shear have been related to
development of atherosclerosis
[3]. Considering the clear importance
of shear stress, much research is devoted to identifying the
mechanisms of shear stress sensing, the intracellular processes
that occur in response to altered shear stress patterns, and
the functional and structural consequences. The paper by Brakemeier
et al., in this issue
[4], shows that expression of intermediate-conductance
calcium-activated potassium channel in human umbilical vein
endothelial cells (HUVECs) is upregulated by arterial shear
stress. The authors suggest that such upregulation could form
a mechanism for long-term adaptation of endothelial cells to
altered blood flow
[4].
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2. Intermediate-conductance calcium-activated potassium (IKCa) channels in EC
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Endothelial cells express a vast array of ion channels
[5].
Potassium channels in ECs include ATP-sensitive, inwardly rectifying,
and Ca
2+-activated channels. The latter group of channels is
activated by a rise in local intracellular calcium. They include
large-, intermediate-, and small-conductance channels (BK
Ca,
IK
Ca, and SK
Ca, respectively). IK
Ca channels have a single channel
conductance of 15 pS in normal concentrations of extracellular
K
+ [5]. The channels have a calmodulin binding site that is
responsible for their calcium sensitivity. The channels are
blocked by charybdotoxin and clotrimazole, but not by apamin
(which blocks SK
Ca) or iberiotoxin (a blocker of BK
Ca)
[6].
Recently, a structural analogue of clotrimazole, TRAM-34, has
been developed as a selective blocker for IK
Ca channels
[7].
1-EBIO is an effective and more or less selective opener for
IK
Ca channels
[8].
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3. Upregulation of IKCa channels by shear stress
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The genes coding for IK
Ca and SK
Ca channels comprise four members,
KCNN1–KCNN4; the article by Brakemeier studies expression
of the
KCNN4 (
IKCa1) gene
[9]. The authors observed that in
HUVECs, 15 dyn/cm
2, reflecting arterial levels of shear stress,
causes an eight-fold upregulation of
IKCa1 mRNA after 4 h, which
persisted at four-fold baseline levels after 24 h of shear.
At lower shear levels (5 dyn/cm
2),
IKCa1 upregulation occurred
after 24 h. The persistence of upregulation suggests that this
is a true adaptation process to increased shear stress, as also
found for eNOS
[10], rather than an ‘activation’
response such as upregulation of the adhesion molecule ICAM-1.
Importantly, the authors also show the functional consequences
of shear-induced
IKCa1 upregulation. Thus, in whole-cell patch-clamp
experiments, IK
Ca currents in response to Ca
2+ dialysis increased
strongly after culture under shear. In addition, confluent HUVEC
monolayers grown under shear had similar membrane potentials
as their static controls, but hyperpolarizing responses to the
endothelium-dependent dilator ATP and to the IK
Ca opener 1-EBIO
were strongly enhanced in the cells grown under shear. The authors
finally show the involvement of the MEK/ERK pathway in the upregulation
of
IKCa1.
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4. Role of IKCa channels in endothelium-dependent dilation
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The importance of potassium channels in general for endothelial
function relates partly to calcium signaling and subsequent
production of endothelium-derived factors
[11]. Opening of potassium
channels causes hyperpolarization and thus increases the driving
force for calcium entry. This leads to a rise in intracellular
calcium provided that pathways for calcium entry are simultaneously
open. On the other hand, calcium-activated potassium channels
act downstream of a rise in endothelial calcium. In particular,
endothelial IK
Ca and SK
Ca channels have been implicated in endothelium-derived
hyperpolarizing factor (EDHF)-mediated dilation
[12–14].
Thus, an elevation of endothelial calcium causes opening of
these channels, a rise in extracellular potassium in the space
between EC and SMC, and subsequent opening of inward rectifying
potassium channels and hyperpolarization of the SMC
[15]. Alternatively,
it has been suggested that the endothelial hyperpolarization
can be transmitted directly to the SMC through gap junctions
between EC and SMC
[16,17]. Through either of these mechanisms,
the observed upregulation of IK
Ca channels under shear would
contribute to a larger EDHF response in EC preconditioned to
arterial shear levels.
There is no evidence that IKCa channels act as primary shear sensors. Rather, these channels could participate in an EDHF pathway downstream from the shear stimulus. One could question what the function would be of shear stress upregulating its own signaling system in endothelial cells. Part of this may relate to the lack of NO bio-availability in many cardiovascular pathologies [18]. A lack of NO-dependent shear-induced vasodilation would cause deeper constriction and inward remodeling. This would increase shear stress, which is inversely proportional to the cube of the vessel diameter. Upregulation of eNOS and IKCa channels would then allow the cell to respectively produce more NO and increase the contribution of NO-independent dilator pathways such as IKCa-driven EDHF, thereby restoring the cell's shear stress sensitivity and normalizing diameter and shear stress. Indeed, strong EDHF contributions to flow-dependent dilation have been observed in eNOS knockout mice [19] and diseased human coronary vessels [20].
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5. HUVECS as models for shear stress studies
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The study by Brakemeier et al.
[4] was performed on HUVECs,
grown in a cone-and-plate viscosimeter. HUVECs form a convenient
and widely used source of human endothelial cells, and much
has been learned and can still be learned from this cell type.
It makes sense to study the effects of arterial shear stress
levels on phenotype of these venous cells for two reasons. Specifically,
it may provide information on the adaptation processes in venous
bypass grafts. In a broader perspective, such studies help in
understanding the contribution of disturbed shear stress profiles
to local endothelial dysfunction and atherosclerosis. The paper
by Brakemeier et al. makes an important contribution to this
field of research. However, future work will be required to
establish whether the currently found upregulation of
IKCa1 under shear also occurs in arterial EC, and whether arterial
and venous EC differ in their basal expression levels of this
channel.
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References
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1. Introduction
2. Intermediate-conductance...