Endothelial Cell Ion Channel Expression and Function in Arterioles and Resistance Arteries

Jackson, William F.

doi:10.1007/978-3-319-29635-7_1

William F. Jackson³

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7 Citations

Abstract

Ion channels importantly contribute to the function of endothelial cells. They serve as the major source of intracellular Ca²⁺, which, in turn, controls the production of endothelium-derived vasodilators, the permeability of the endothelium, gene expression, and other properties of endothelial cells. In addition, the activity of ion channels determines the membrane potential of endothelial cells that serves as an important signal for cell-cell communication between endothelial cells and between endothelial cells and overlying smooth muscle cells, and may feed-back to regulate the activity of the ion channels themselves. This review provides an overview of the expression and function of endothelial ion channels that contribute to Ca²⁺ and membrane potential signaling that is involved in the regulation and modulation of vasomotor tone of resistance arteries and arterioles. Channels discussed include inositol 1,4,5 trisphosphate receptors that mediate agonist-induced Ca²⁺ release from endoplasmic reticulum stores; members of the transient receptor potential family and other channels that mediate agonist-induced Ca²⁺ influx through the plasma membrane; Ca²⁺-activated K⁺ channels that mediate agonist-induced membrane hyperpolarization; and inward rectifier K⁺ channels that serve as sensors for changes in extracellular K⁺ and amplifiers of hyperpolarization induced by the activity of other ion channels. It is emphasized that all of these channels exist as members of macromolecular signaling complexes providing a rich environment for regulation of their activity and the function of endothelial cells in resistance arteries and arterioles.

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Keywords

Introduction

Endothelial cells express a diverse array of ion channels in their plasma membranes and in the membranes of intracellular organelles that contribute to the function of these cells. These channels provide the major source of intracellular Ca²⁺ that serves as an important second messenger controlling the activity of Ca²⁺-dependent ion channels and cell membrane potential [40], endothelial cell production of NO, prostaglandins and epoxides of arachidonic acid (EETs) [40] and regulating barrier function of the endothelium [52, 90]. Intracellular Ca²⁺ is also an important signal controlling gene expression in [117, 130] and proliferation of [120, 123] endothelial cells. Ion channels also participate in cell volume regulation [70]. In addition, plasmalemmal ion channel activity importantly contributes to the membrane potential of endothelial cells that serves as a major signal for cell-cell communication between adjacent endothelial cells and as well as overlying smooth muscle cells due to the expression of homocellular and heterocellular gap junctions in the vascular wall [29]. Membrane potential may also feedback to affect Ca²⁺ influx through plasmalemmal Ca²⁺ permeable ion channels by influencing the electrochemical gradient for Ca²⁺ influx [65, 66, 69, 123], although this topic remains controversial [23, 34, 108, 113, 158]. Thus, ion channels importantly contribute to the function of endothelial cells in health and disease. This review will focus on the expression and function of endothelial ion channels involved in the regulation of vasomotor tone in resistance arteries and arterioles. Because there are considerable changes in ion channel expression and function during proliferation of cells in culture [11, 12, 20, 123, 135], emphasis will be placed on evidence from intact blood vessels and from freshly isolated endothelial cells from the peripheral circulation. The reader is also directed to a number of outstanding earlier reviews of ion channels in endothelial cells for access to earlier literature on this topic [123–125].

Setting the Stage

Most vasodilators that produce endothelium-dependent vasodilatation (see [79]) act on Gα_q-protein-coupled receptors which are linked to phospholipase C (PLC)-β producing inositol-1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG) from membrane phospholipids [13] (Fig. 1.1). The released IP₃ activates IP₃R in the membranes of the smooth endoplasmic reticulum, releasing stored Ca²⁺ and increasing cytosolic Ca²⁺ [13]. The activation of IP₃R, loss of Ca²⁺ from intracellular Ca²⁺ stores and the DAG produced by PLC-β, activate plasma membrane Ca²⁺-permeable ion channels [51], allowing Ca²⁺ to diffuse down its electrochemical gradient into the cells, producing a steady-state increase in intracellular Ca²⁺ (Figs. 1.1 and 1.2). The sum of these two major events (the release of ER-stored Ca²⁺ via IP₃R and the influx of Ca²⁺ via plasmalemmal ion channels) produces the well-described, agonist-induced cytosolic Ca²⁺ transient in endothelial cells (see Fig. 1.2). The increase in intracellular Ca²⁺ then activates plasmalemmal Ca²⁺-activated K⁺ channels to produce hyperpolarization of the endothelial cell membrane as shown in Fig. 1.2c, as well as activation of other Ca²⁺-dependent processes such as NO production and release of arachidonic acid from membrane phospholipids resulting in increased production of prostacyclin and epoxides of arachidonic acid [40] (Fig. 1.1). The remainder of this review will focus on the expression and function of ion channels responsible for agonist-induced Ca²⁺ signals and membrane hyperpolarization in endothelial cells as shown in Fig. 1.2, as well as other endothelial cell ion channels that appear important to the regulation of myogenic tone in resistance arteries and arterioles.

What Endoplasmic Reticulum Ion Channels Mediate Agonist-Induced Ca²⁺ Signals?

Inositol-1,4,5-trisphosphate Receptors

Early studies demonstrated that agonists of Gα_q-coupled receptors increased intracellular Ca²⁺ in endothelial cells that was due to an initial release of Ca²⁺ from internal stores followed by Ca²⁺ influx [18, 25, 59, 139, 142, 143] (Figs. 1.1 and 1.2). Pharmacological studies subsequently identified IP₃Rs as the primary Ca²⁺ release channel responsible (see [23, 143] and Fig. 1.2 for examples). Inositol-1,4,5-trisphosphate receptors are large (350 kDa) tetrameric Ca²⁺ release channels found in the endoplasmic reticulum of all mammalian cells [47, 104]. Each monomer contains an IP₃-binding domain that is located in cytoplasmic N-terminus of the proteins [47, 104]. Calcium appears to be the trigger for gating IP₃ channels to open (see Table 1.1 for EC₅₀ values for activation of the channels) [47, 104]. However, the response to increases in Ca²⁺ is biphasic, with higher concentrations of Ca²⁺ becoming inhibitory (Table 1.1) [47, 104]; Ca²⁺ activates the channels at low concentrations, but inhibits Ca²⁺ release at high concentrations (see Fig. 7 in [47] for examples). It has been proposed that the concentration of IP₃ determines the affinity of IP₃Rs for the inhibitory effects of elevated Ca²⁺; as the concentration of IP₃ increases, higher levels of Ca²⁺ are required to inhibit the channels (Table 1.1) [47, 104]. Thus, the concentration of IP₃ effectively determines the range of cytosolic Ca²⁺ concentration over which the IP₃Rs will be active [47]. However, this has not been observed in all systems [171]. Nonetheless, in the presence of physiologically relevant concentrations of IP₃, IP₃R can undergo Ca²⁺-induced-Ca²⁺ release (CICR ) providing a positive feedback mechanism for release of Ca²⁺ from adjacent IP₃R (as in the case of Ca²⁺ waves ), as well as amplification, with a limit, of Ca²⁺ signals originating from Ca²⁺ influx through overlying plasma membrane ion channels.

Table 1.1 Microvascular endothelial ion channels and their pharmacology

Full size table

There are three isoforms of IP₃R, IP₃R1, 2 and 3 originating from three genes with modestly different characteristics (see Table 1.1); IP₃R2 and 3 appear to have the highest sensitivity for Ca²⁺-induced activation with IP₃R3 having the lowest sensitivity for IP₃ [47, 104, 171]. In addition to IP₃ and Ca²⁺, the activity of IP₃Rs is also sensitive to cytoplasmic ATP concentrations [47, 104, 171]. In IP₃R1 and 3, ATP produces a leftward shift in the Ca²⁺-activity relationship increasing the affinity of the channels for Ca²⁺, with little effect on the maximal open-state probability [47, 171]. In distinct contrast, ATP has no effect on Ca²⁺-sensitivity of IP₃R2 receptors, but has large effects on the maximum open-state probability of the channels; low ATP severely reduces the maximal activity of IP₃R2 [104, 171]. Given that IP₃Rs exist in signaling microdomains adjacent to ATPases in the ER and in the plasma membrane, local ATP concentrations could have a profound effect on IP₃R function in an isoform-specific fashion. Finally, IP₃R interact with a large number of proteins in the cytosol and in the lumen of the ER that can modulate the activity of these channels by protein-protein interactions, and phosphorylation/dephosphorylation in the case of protein kinases and phosphatases [47, 159].

Freshly isolated rat aortic endothelial cells express transcripts for all three isoforms of IP₃R with IP₃R1 being most highly expressed [118, 119]. Endothelial cells from mouse mesenteric arteries express transcripts for all three isoforms with IP₃R2 being most highly expressed [93]. Mouse cremaster arteriolar endothelial cells also express transcripts for all three isoforms, but IP₃R3 appears to be most highly expressed (Fig. 1.4a), and protein expression for all three isoforms has been reported [77]. All three IP₃R isoforms were detected in the endothelium of Wistar rat basilar and mesenteric arteries by immunocytochemistry [56]. Thus, it appears that there may be regional or species-dependent differences in the expression of IP₃R isoforms, and little is known about the localization or function of the individual IP₃R isoforms in native endothelial cells.

In co-cultures of smooth muscle and endothelial cells from mouse cremaster arterioles , and in intact vessels, it has been reported that IP₃R1 localizes at sites of myoendothelial gap junctions (MEJs ) [77]. Similarly, in intact mouse mesenteric resistance vessels , there are clusters of IP₃Rs near holes in the internal elastic lamina [93], sites that have been correlated with projections of endothelial cells (myoendothelial projections, MEPs , Fig. 1.3) towards overlying smooth muscle cells and the localization of MEJs [136]. However, the IP₃R isoform expressed in these clusters was not identified. Importantly, these sites were shown to generate localized endothelial cell Ca²⁺ events that have been termed Ca²⁺ pulsars [93]. These events are too small and rapid to be detected by global Ca²⁺ measurements made with Fura 2 (Fig. 1.2, for example), but can be detected using Fluo-4 or genetic Ca²⁺ sensors such as GCaMP2 and high-speed confocal imaging [83, 93]. Previous studies have shown that K_Ca3.1 channels also are clustered in the same microdomain [137] providing a means for Ca²⁺ pulsars to be translated into, for example, changes in membrane potential (see below for more on this topic). In addition, a growing list of proteins congregate in the vicinity of MEJs including TRPA1 channels [37], TRPV4 channels [149, 150], anchoring proteins (e.g., AKAP150 [150]), protein kinases (e.g., PKC [150]), nitric oxide synthase [151], Na⁺/K⁺ ATPase [33] and other proteins [152].

Calcium pulsars [83, 93] and Ca²⁺ waves [36, 83] are present under resting conditions in endothelial cells of pressurized vessels [83, 93] and likely contribute to the resting activity of K_Ca3.1 channels (in the case of pulsars and waves) and K_Ca2.3 channels (Ca²⁺ waves) and endothelial cell membrane potential. Endothelium-dependent vasodilators , such as acetylcholine [93, 147] or adenosine [36], increase the number and frequency of Ca²⁺ pulsars [93], and also recruit IP₃R located throughout endothelial cells to produce asynchronous [93, 147] or synchronous [36, 147] Ca²⁺ waves and increases in global Ca²⁺ (Fig. 1.2). Thus, the global Ca²⁺ signals that have been reported in native microvascular endothelial cells [23, 32, 107, 148] represent a complex mixture of local Ca²⁺ pulsars and Ca²⁺ waves in addition to more homogeneous increases in cytosolic Ca²⁺. Additional studies are needed to define the precise localization of IP₃R isoforms and their function related to endothelium-dependent vasomotor activity.

Ryanodine Receptors

Ryanodine receptors (RyR) are composed of very large protein subunits (~500 kDa) that form Ca²⁺-sensitive-Ca²⁺-release channels in the endoplasmic reticulum [61]. Similar to IP₃R, they are tetramers with three isoforms from three distinct genes: RyR1, RyR2 and RyR3 [61, 62, 185]. Skeletal muscle expresses predominantly RyR1, the heart expresses predominantly RyR2 and RyR3 is expressed in the brain and other tissues [61, 62, 185]. Vascular smooth muscle cells may express all three isoforms, with RyR2 being predominant in resistance artery [166] and arteriolar smooth muscle cells [178]. Immunofluorescence demonstrated RyR expression in guinea pig endocardium and aortic endothelial cells [95], and ryanodine binding sites have been reported in porcine coronary artery endothelial cells [54]. Studies of cultured endothelial cells suggest expression of functional ryanodine receptors [191], and freshly isolated endothelial cells from rabbit aorta display caffeine-induced Ca²⁺ transients implying the presence of RyR in these cells [132]. In porcine coronary artery endothelial cells, caffeine elicits a Ca²⁺ transient in only 37 % cells studied suggesting heterogeneity of the distribution and function of endothelial RyR [55]. Transcripts for RyR3, but not RyR1 or RyR2 have been reported in endothelial cells freshly isolated from human mesenteric arteries [89]. Thus, RyR appear to be expressed and functional in macrovascular endothelial cells . However, there is little evidence for expression of ryanodine receptors in microvascular endothelial cells. In mouse mesenteric resistance arteries , where expression of IP3Rs are readily detected, no message for the three RyR isoforms were found, and ryanodine had no effect on basal or acetylcholine-stimulated Ca²⁺ events [93]. We have also found lack of expression of the three RyR isoforms in endothelial cells from mouse cremaster arterioles (Fig. 1.4b), and caffeine does not elicit a Ca²⁺ transient in freshly isolated hamster cremaster arteriolar endothelial cells [23] (Fig. 1.5a), although lack of effect of caffeine on global Ca²⁺ levels does not completely exclude a role for RyR [126]. A lack of effect of the RyR antagonist, ryanodine, on Ca²⁺ signals in endothelial cells in rat mesenteric arteries also has been observed [83]. Although species and regional heterogeneity in the expression of RyR cannot be excluded, these data suggest that RyR do not play a major role in Ca²⁺ signaling in endothelial cells of resistance arteries and arterioles.

What Ion Channels Mediate Agonist-Induced Ca²⁺ Influx?

TRP Channels

Endothelium-dependent vasodilators not only increase the activity of IP₃R, by stimulating the production of IP₃, they also result in the activation of ion channels in the plasmalemma of endothelial cells that conduct Ca²⁺ and are responsible for steady-state increases in intracellular Ca²⁺ (i.e., the plateau phase of the Ca²⁺ transient shown in Fig. 1.2). Early studies in cultured endothelial cells provided evidence that agonist-induced Ca²⁺ entry was electrophysiologically and pharmacologically similar to the Ca²⁺ entry induced by depletion of intracellular Ca²⁺ stores [139, 142, 143, 164, 165]. In primary cultures of porcine coronary artery endothelial cells, substance P activates a non-selective, inward whole-cell cation current that can be completely inhibited by blocking IP₃-dependent activation of IP₃R with heparin [143]. Similarly, block of IP₃R with xestospongin-D abolishes methacholine-induced global Ca²⁺ transients in arteriolar endothelial cells [23] (Fig. 1.2e). These data suggest that, at least under the conditions of these experiments, agonist-induced activation of IP₃R , and likely release of Ca²⁺ from internal stores is required to activate the Ca²⁺ influx pathway that is responsible for the plateau phase of the agonist-induced global Ca²⁺ transients, and hence the steady-state phase of agonist-induced endothelial cell hyperpolarization. This does not exclude the activation of receptor, or second-messenger activated Ca²⁺ influx as the currents activated may be too small to detect by conventional whole-cell methods, or may produce only local changes in Ca²⁺ that do not influence global Ca²⁺, particularly as detected by Fura-2.

The ion channels that are responsible for agonist-induced Ca²⁺ influx in native endothelial cells remain in question. Several members of the transient receptor potential (TRP) family of ion channels, in particular TRPC1, TRPC3, TRPC4, TRPC6 and TRPV4, along with members of the stromal interaction molecule (STIM) and ORAI families appear to be likely candidates, and it is also likely that multiple channels are activated and contribute to the Ca²⁺ influx activated by endothelium-dependent vasodilators (Fig. 1.1).

The TRP channel family form, in general, cation channels that are weakly Ca²⁺ selective (permeability for Ca²⁺/permeability for Na²⁺ <10) [179]. The channel monomers are assumed to have six membrane spanning domains with the pore between segments 5 and 6, and both the C- and N-termini of the channels located intracellularly, with four monomers forming a functional channel [179].

Endothelial cells express TRPC1 , which may serve as store-operated Ca²⁺ channels in endothelial cells [124]. However, their function in agonist-induced endothelial hyperpolarization and vasodilatation remains unclear. This may partly be due to the observation that TRPC1 heteromultimerize with other members of the TRPC family (especially TRPC4) as well as STIM/ORAI containing channels [30]. Studies of cultured human pulmonary artery endothelial cells revealed expression of TRPC1, and that antisense oligonucleotide knockdown reduced Ca²⁺ influx induced by Ca²⁺ store depletion by about 50 % suggesting that TRPC1 contributes to the Ca²⁺ influx pathway in these cells [17]. A similar conclusion was drawn in cultured bovine aortic endothelial cells using a TRPC1 antibody to inhibit basic fibroblast growth factor-induced Ca²⁺ entry [7]. Studies of human and mouse pulmonary microvascular endothelial cells also support a role for TRPC1 in agonist- and Ca²⁺ store depletion-induced Ca²⁺ entry and microvascular permeability [5, 92, 114, 155, 156]. However, the roles played by TRPC1 in agonist-induced endothelial cell hyperpolarization and vasodilatation is not as clear. Study of carotid artery endothelial cells from TRPC1 knock-out mice reveal enhanced acetylcholine-induced hyperpolarization, rather than decreased responses predicted based on studies of cultured cells and lung models [140]. Although compensatory upregulation of expression of other channels might explain these results, prior experiments failed to detect upregulation of other TRPC channels [31]. At the least, these results indicate that TRPC1 is not essential for agonist-induce endothelial cell hyperpolarization and that additional channels contribute to the Ca²⁺ influx induced by agonists in native endothelial cells, although regional heterogeneity in expression and function cannot be excluded. In contrast, studies of native aortic endothelial cells from TRPC1^−/− mice demonstrated a small reduction of endothelial cell Ca²⁺ transients induced by acetylcholine [87], suggesting that TRPC1 channels do participate, to a small extent, in agonist-induced Ca²⁺ signals. A small reduction in thrombin-induced Ca²⁺ transients was also observed after siRNA knock down of TRPC1 in cultured pulmonary microvascular endothelial cells [155]. Taken together, these data do not support a major role for TRPC1 in agonist-induced Ca²⁺ entry into endothelial cells relevant to endothelial cell hyperpolarization and vasodilatation.

TRPC4 is another channel that has been implicated in agonist and store-depletion-induced Ca²⁺ entry into endothelial cells [48, 155, 162]. In cultured aortic endothelial cells isolated from TRPC4^−/− mice, the plateau phase of agonist-induced Ca²⁺ transients and related endothelial cell hyperpolarization was substantially depressed (but not eliminated) [48], suggesting a major role for TRPC4 in agonist-induced Ca²⁺ transients in macrovascular endothelial cells. Similarly, use of cultured, pulmonary microvascular endothelial cells isolated from TRPC4^−/− mice, as well as siRNA knock down of endogenous TRPC4 from cells isolated from wild-type mice demonstrated a major role for TRPC4 in thrombin- and Ca²⁺-store-depletion-induced Ca²⁺ signals [155]. The authors also demonstrated that expression of STIM1 was necessary for normal store-operated Ca²⁺ entry and showed that STIM1 and TRPC4 interacted and that expression of both proteins was required for normal Ca²⁺ signaling [155]. Endothelium-dependent vasodilatation is also substantially reduced in vessels from TRPC4^−/− mice [48]. These data support a role for TRPC4 as a Ca²⁺ influx pathway during agonist-induced Ca²⁺ signaling, with activity triggered by loss of Ca²⁺ from internal stores as sensed by STIM1 (Fig. 1.1).

In human umbilical vein endothelial cells , the Ca²⁺ influx induced by agonists or depletion of intracellular stores depends on expression of STIM1 and ORAI1 with STIM1 serving as the sensor of ER Ca²⁺ and ORAI1 forming the pore of the store-operated channels [1, 155, 190]. Furthermore, in contrast to the studies outlined above, it was shown that effective knock down of TRPC1 or TRPC4 had no effect on Ca²⁺ store depletion-induced Ca²⁺ signals in this model [1]. However, studies in murine pulmonary microvascular endothelial cells indicate that expression of ORAI1 is not required for normal endothelial cell Ca²⁺ signaling [155]. These data suggest that there may be regional or species-dependent differences in the ion channels responsible for agonist-induced Ca²⁺ signaling in endothelial cells. The role played by STIM1 and ORAI1 in agonist-induced endothelial cell hyperpolarization of endothelial cells in resistance arteries and arterioles has not been reported.

TRPV4 channels also participate in agonist- and shear-stress-induced Ca²⁺ signals in endothelial cells, and endothelium-dependent vasodilatation in intact vessels [8, 35, 39, 109, 149, 150, 187]. These channels are temperature sensitive [175], stretch-sensitive [170] and can be activated by EETs (Fig. 1.1) and phorbol ester derivatives [170]. Calmodulin interacts with the C-terminal domain and mediates Ca²⁺-dependent activation of these channels [153]. Activation of TRPV4 channels in endothelial cells increases intracellular Ca²⁺ [109, 149, 150, 174, 187] and produces vasodilatation [39, 134, 149, 150, 187]. Importantly, the plateau-phase of vasodilator agonist-induced endothelial cell Ca²⁺ transients are reduced in the endothelium of vessels from TRPV4^−/− mice [149, 150, 187]. In mouse mesenteric arteries, TRPV4 channels cluster in the same microdomain as IP₃R at MEPs (Fig. 1.3), and endothelium-dependent agonists activate these channels to produce TRPV4-Ca²⁺ sparklets at the sites of MEPs [149, 150]. Activation of Ca²⁺ influx through only a few TRPV4 channels per endothelial cell activates endothelial K_Ca2.3 and K_Ca3.1 channels and can produce maximal vasodilatation, with activation of K_Ca3.1 channels, which also cluster at MEJ’s, occurring preferentially at low levels of TRPV4 activation [149]. Block of TRPV4 channels with HC-067047 in mouse mesenteric arteries substantially inhibits the component of acetylcholine-induced vasodilatation that is mediated by activation of endothelial K_Ca2.3 and K_Ca3.1 channels, suggesting that TRPV4 channels play a major role in agonist-induced Ca²⁺ influx that contributes to endothelial cell hyperpolarization and subsequent vasodilatation [149]. In mouse mesenteric arteries, muscarinic receptor agonists activate TRPV4 channels through a signaling pathway involving PLC-β and activation of PKC that is targeted to the channel by the scaffolding protein, AKAP150 [150] (Fig. 1.1). Thus, TRPV4 appears to play a major role in agonist-induced endothelial cell Ca²⁺ signaling that is related to hyperpolarization and vasodilatation.

Evidence also has been presented suggesting that TRPC3 is involved in agonist-induced Ca²⁺ signaling in endothelial cells [75, 86, 87, 98, 141, 184]. These TRP channels can be activated by DAG formed through the action of PLCs on membrane phospholipids [71] (Fig. 1.1). In cerebral vascular smooth muscle, activation of IP₃R1, independent from release of Ca²⁺, results in activation of TRPC3 [4]. It is not known if a similar interaction occurs in endothelial cells. TRPC3 is involved in flow- and bradykinin-induced vasodilatation in rat small mesenteric arteries, but not dilation induced by histamine, ATP or cyclopiazonic acid [98]. As with TRPV4, TRPC3 appears to cluster near MEPs in rat mesenteric resistance artery endothelial cells [141]. In rat mesenteric arteries, the TRPC3 blocker, Pyr3, inhibited endothelial cell hyperpolarization and the portion of acetylcholine-induced endothelium-dependent vasodilatation mediated by activation of K_Ca2.3 and K_Ca3.1 channels and the consequent endothelial cell hyperpolarization [141]. These data suggest a close physical and functional relationship between TRPC3 and the K_Ca channels that mediate agonist-induced endothelial cell hyperpolarization. In contrast, in porcine coronary arteries, the TRPC3 antagonist Pyr3 inhibited the portion of bradykinin-induced vasodilatation that is mediated by NO, NO production in isolated endothelial cells and bradykinin-induced endothelial cell Ca²⁺ transients suggesting that TRPC3 channels contributed to Ca²⁺ signaling directed at NO production in this system [75]. In murine cerebral arteries, ATP-induced endothelial cell Ca²⁺ transients are reduced by Pyr3 or in cells isolated from TRPC3^-/- mice, and Ca²⁺ entry through TRPC3 appears to selectively activate K_Ca2.3 channels during the plateau-phase of agonist-induced endothelial cell hyperpolarization [86]. Thus, there appear to be regional and likely species-dependent differences in the roles played by TRPC3 in endothelial cell Ca²⁺ signaling and hyperpolarization. This likely represents differences in the localization of the channels and the signaling microdomains in which they are expressed.

Endothelial cells in cerebral arteries also express TRPA1 channels that, when activated, produce endothelial cell hyperpolarization and endothelium-dependent vasodilatation [37, 154]; the endothelium of mouse, rat or human coronary, renal or mesenteric arteries do not express transcripts or protein for TRPA1 [154]. The TRPA1 subunits have 14–18 ankyrin repeats at their amino-terminal that give the channels their name, are activated by a diverse array of chemicals including pungent substances found in mustards and garlic and are heavily expressed in sensory nerves [9]. In endothelial cells of cerebral arteries, these channels cluster at MEPs and co-localize with K_Ca3.1 channels [37, 38, 154] (Fig. 1.3). Activation of TRPA1 leads to TRPA1-Ca²⁺ sparklets [154]. Vasodilatation induced by activation of TRPA1 channels with allyl isothiocyanate (AITC) in substantially inhibited by the K_Ca3.1 blocker, TRAM34 and abolished by the combination of TRAM34 and the K_Ca2.3 blocker, apamin, but is unaffected by blockade of nitric oxide synthase or cyclooxygenase [37, 154]. These data indicate that Ca²⁺ influx through TRPA1 primarily activates endothelial cell K_Ca channels to produce vasodilatation. Furthermore, as with TRPV4 channels [149], only a small number of active TRPA1 channel clusters per endothelial cell are required for maximal vasodilatation [154]. It was also shown that vasodilatation induced by AITC could be inhibited by Ba²⁺ suggesting that inward rectifier K⁺ channels either amplify the hyperpolarization induced by activation of endothelial cell K_Ca channels, or transduce the endothelial cell K_Ca channel activation by detecting the K⁺ released through the K_Ca channels [37] (Fig. 1.1). In the endothelium of cerebral arteries, TRPA1 co-localizes with NADPH oxidase (NOX) isoform 2, and lipid peroxides produced by NOX2 activate these channels to produce vasodilatation [154].

Expression and function of TRPV3 channels in rat cerebral artery endothelial cells also has been reported [38]. These channels appear to be more uniformly expressed than TRPV4 or TRPA1 [38]. Activation of TRPV3 with agents such as the oregano monoterpenoid phenol, carvacrol, increases endothelial cell Ca²⁺ and activates endothelial cell K_Ca channels to produce endothelial cell hyperpolarization and vasodilatation [38].

Finally, endothelial cells also express TRPC6 that appears to contribute to Ca²⁺ signaling [21, 60, 100, 127, 145]. As for TRPC3, TRPC6 is activated by DAG produced simultaneously with the formation of IP₃ by PLCs [71] (Fig. 1.1 and Table 1.1). Human pulmonary artery endothelial cells express TRPC6, and siRNA knockdown of this channel impairs Ca²⁺ signaling and increases monolayer permeability induced by thrombin [145]. Human dermal microvascular endothelial cells in culture express TRPC6, but not TRPC3, and the plateau phase of the histamine-induced increase in Ca²⁺ is reduced by SKF96365 in these cells. Furthermore, histamine-induced increases in microvascular permeability are abolished in TRPC6^−/− mice supporting a role for this channel in regulation of microvascular Ca²⁺ signaling and permeability [21]. Increased microvascular permeability induced by vascular endothelial growth factor (VEGF) appears to be mediated by TRPC6 [127], and VEGF-induced Ca²⁺ transients are reduced in cultured human microvascular endothelial cells expressing a dominant-negative form of TRPC6 [60]. Mouse aortic endothelial cells express TRPC6 and TRPC3, but carbachol-induced Ca²⁺ transients in isolated endothelial cells as well as carbachol-induced endothelium-dependent relaxation of aortas are reduced only in vessels isolated from TRPC6^−/− mice [100]. The role of TRPC6 in agonist-induced Ca²⁺ signaling related to vasodilatation of arterioles and resistance arteries remains to be established.

Taken together, these data suggest that it is likely that there are multiple ion channels in the plasma membrane of endothelial cells that conduct Ca²⁺ into the cells to activate endothelial cell K_Ca channels (and other processes) to produce endothelial cell hyperpolarization (Fig. 1.1). Agonists that activate Gα_q-coupled receptors appear to activate multiple channels including TRPC3, TRPC4, TRPV4 and possibly TRPC6 (Fig. 1.1). However, the roles played by each of these channels, together, in concert, remains to be established. Regional and species dependent heterogeneity in expression and function of these channels cloud our view of the larger picture. The use of isolated, intact blood vessels using multiple approaches (as for studies of TRPV4 [149, 150]) appears to be a step in the right direction in solving this puzzle.

Voltage-Gated Ca²⁺ Channels

The expression of voltage-gated Ca⁺ channels (VGCC ) in endothelial cells is controversial. Capillary endothelial cells from bovine adrenal medullas were reported to express both L-type and T-type VGCC as assessed by patch clamp techniques [167]. However, the function of these channels was not defined. More recently, mouse and rat pulmonary microvascular endothelial cells have been shown to express CaV3.1-based T-type VGCC that appear to be involved in thrombin-induced Ca²⁺ signals, cell adhesion, exocytosis of von Willebrand’s Factor and depolarization-induced Ca²⁺ signaling [177, 180, 189]. Endothelial cells of mesenteric arterioles label with antibodies for CaV3.2, but not CaV1.2 or CaV3.1 and these channels were proposed to participate in conducted vasomotor responses [16]. Immunofluorescence identified CaV3.1 and CaV3.2 in endothelial cells in rat middle cerebral artery and its branches, although their function was not studied [91]. In mouse mesenteric arteries, CaV3.1 has been detected in the endothelium by immunofluorescence, was colocalized with eNOS and appeared to play a role in depolarization-induced NO synthesis based on studies employing CaV3.1 knockout mice [157]. In mouse cremaster muscle arterioles, CaV3.2 has been implicated in electrically-induced, conducted vasodilatation based on the pharmacology of this response [45]. However, the location of the channel was not established. Thus, there appears to be some evidence for expression of T-type channels in endothelial cells of resistance arteries and arterioles. However, their electrophysiological function has not been adequately explored in other than cultured cells, particularly in the peripheral microcirculation. Whether hyperpolarization of endothelial cells induced by vasodilators can activate current through T-type channels by reducing voltage-dependent inactivation and recruiting a window-current has not been established. Depolarization of freshly isolated hamster arteriolar endothelial cells does not, in and of itself, elicit a global change in intracellular Ca²⁺ [23]. These data do not support a major role for VGCC in these endothelial cells.

Which Ion Channels Mediate Agonist-Induced Endothelial Cell Hyperpolarization?

Early studies in endothelial cells from conduit arteries and in cultured cells showed that agonists of Gα_q-protein-coupled receptors resulted in Ca²⁺ signals in endothelial cells [18, 25, 142], activation of endothelial cell Ca²⁺-activated K⁺ channels [18, 24, 25, 53, 142] and endothelial cell hyperpolarization [18, 142].

K_Ca2.3 and K_Ca3.1 Channels

Native endothelial cells in resistance arteries primarily express two types of K_Ca channels: K_Ca2.3, the small-conductance, K_Ca (SK_Ca) channel and K_Ca3.1, the intermediate-conductance K_Ca (IK_Ca) channel [41, 57, 88, 137, 144, 160]. The channels are the products of distinct genes (KCNN3 and KCNN4, respectively [176]) (Table 1.1). Both channels are voltage insensitive and use calmodulin as the Ca²⁺ sensor, which interacts with the intracellular C-terminus of both channels to gate channel opening [44, 182]. The concentration of free Ca²⁺ required for 50 % of maximal activation of both K_Ca2.3 [182] and K_Ca3.1 [78] is on the order of 300 nM, with the threshold for activity at approximately 100 nM and maximal activity at 1 μM [78, 182]. These channels display distinct pharmacology that has aided in elucidating their function in intact vessels (Table 1.1).

Both K_Ca2.3 and K_Ca3.1 can contribute to endothelial cell hyperpolarization induced by agonists of Gα_q-protein coupled receptors , such as acetylcholine acting at M₃-muscarinic receptors: for example, in guinea-pig carotid artery [26], rat mesenteric arteries preconstricted with phenylephrine [27] and porcine coronary arteries [19], inhibition of agonist-induced hyperpolarization requires block of both K_Ca2.3 and K_Ca3.1. However, in several systems, agonist-induced hyperpolarization of endothelial cells appears to be mediated by K_Ca3.1 alone. In rat middle cerebral arteries , block of K_Ca3.1 alone abolishes endothelial cell hyperpolarization and subsequent vasodilatation induced by UTP [108]. Similarly, in mouse carotid arteries and cremaster muscle microcirculation , K_Ca3.1 appear to dominate acetylcholine-induced vasodilatation based on studies using knockouts of K_Ca2.3 or K_Ca3.1 [15].

The distribution of K_Ca2.3 and K_Ca3.1 in the plasma membrane of endothelial cells is neither random nor uniform. In the endothelium of mouse [93] and rat [137] mesenteric resistance arteries and rat cerebral arteries [37], K_Ca3.1 appear to cluster at MEPs (Fig. 1.3), with some of these MEPs containing gap junction proteins (Connexin 40 and 37) and forming gap junctions with overlying vascular smooth muscle cells (MEJs ) (see [136] and references therein). At MEPs and MEJ’s, K_Ca3.1 likely exist in macromolecular signaling complexes with IP₃Rs [93], TRPA1 channels [37], TRPV4 channels [149, 150], anchoring proteins (e.g., AKAP150 [150]), protein kinases (e.g., PKC [150]) and likely G-protein coupled receptors [150]. This localization appears to facilitate activation of K_Ca3.1 channels by local Ca²⁺ signals [37, 93, 149, 150] and transmission of K_Ca3.1-mediated hyperpolarization from endothelial cells to overlying smooth muscle cells via MEJs (Fig. 1.3). In addition, it has been proposed that activation of K_Ca3.1 channels by Ca²⁺ influx through TRPV4 channels has a positive-feedback effect on Ca²⁺ influx through TRPV4 [128] (Fig. 1.1).

In contrast, K_Ca2.3 channels appear to localize on the periphery of endothelial cells [137]. These channels also likely exist in signaling microdomains. In rat mesenteric arteries K_Ca2.3 localizes in cholesterol-rich areas (caveolae or lipid rafts) and colocalizes with caveolin-1 [2]. In rat cerebral arteries, Ca²⁺ influx through TRPC3 channels selectively activates K_Ca2.3 [86], suggesting co-localization of the two channels. The localization of K_Ca2.3 in caveolae adjacent to gap junction plaques between endothelial cells also likely explains why shear-stress-induced dilation is severely attenuated in carotid arteries from mice with conditional knockout of K_Ca2.3 [15]. The differential cellular distribution of K_Ca2.3 and K_Ca3.1 and their respective signaling microdomains likely explain how these channels contribute to different aspects of agonist-induced endothelial cell hyperpolarization [27, 144].

In addition to agonist-mediated events , endothelial cell K_Ca2.3 and K_Ca3.1 appear to be active at rest contributing to endothelial cell membrane potential and the regulation of myogenic tone particularly in small resistance arteries and arterioles. For example, overexpression of K_Ca2.3 hyperpolarizes mouse mesenteric artery endothelial cells and reduces myogenic tone, whereas conditional knockout depolarizes the cells and increases tone [160]. Similarly, blockade of either K_Ca2.3 or K_Ca3.1, or both channels increases myogenic tone in rat cerebral parenchymal arterioles [22, 63]. It is noteworthy that in upstream middle cerebral arteries, under similar conditions, inhibition of K_Ca2.3 and K_Ca3.1 had a smaller effect on myogenic tone than was observed in downstream parenchymal arterioles, despite their importance in agonist-induced vasodilatation [22]. These data suggest that there are regional differences in the roles played by these channels with increased function in the microcirculation.

K_Ca1.1 Channels

The expression and function of Large-conductance Ca²⁺-activated K⁺ (K_Ca1.1) channels in endothelial cells remains controversial [135]. These voltage and Ca²⁺-sensitive K⁺ channels have a much larger conductance (~250 pS) than K_Ca2.3 or K_Ca3.1, are intrinsically sensitive to Ca²⁺ (i.e., they do not require association with calmodulin), and display distinct pharmacology [73] (Table 1.1). These channels are highly expressed in vascular smooth muscle cells [80, 122]. Studies of cultured endothelial cells have repeatedly demonstrated expression and function of K_Ca1.1 channels (see [135] for references). However, the function and expression of K_Ca1.1 in native and freshly isolated endothelial cells is not clear. For example, in patch-clamp studies of freshly isolated endothelial cells from bovine coronary arteries [50], mouse carotid arteries [15], and rat cerebral parenchymal arterioles [63] no currents characteristic of K_Ca1.1 are detected and essentially all Ca²⁺-activated currents are inhibited by the combination of a K_Ca2.3 and a K_Ca3.1 blocker. However, currents through K_Ca1.1 have been recorded in endothelial cells isolated from rats exposed to chronic hypoxia [76, 131] or from endothelial cells acutely exposed to β-methylcyclodextrin to deplete membrane cholesterol [131], effects that could be reversed by exposure of cells to a membrane permeant version of caveolin-1 [131]. These data are consistent with an earlier study in cultured endothelial cells indicating that K_Ca1.1 are targeted to caveolae and that caveolin-1 inhibited the function of K_Ca1.1 in that microdomain [173]. These data suggest that, in some endothelial cells, K_Ca1.1 channels may be silent under normal conditions, but can be upregulated by conditions, such as chronic hypoxia, that disrupt membrane microdomains. This idea is consistent with the hypothesis that K_Ca1.1 expression and function in endothelial cells only occurs during stress or pathological conditions [135]. Immunohistochemical localization of K_Ca1.1 has been reported in rat cremaster arterioles [163]. There must be regional or species differences in expression of K_Ca1.1 because no transcripts or protein for K_Ca1.1 were detected in bovine coronary artery endothelial cells [50] excluding the possibility that there are silent K_Ca1.1 present in these cells. We also have not detected transcripts for K_Ca1.1 channels in endothelial cells isolated from mouse cremaster arterioles or upstream feed arteries (n = 5 endothelial cell isolates from five mice, Jackson, unpublished observations). Additional studies where message, protein expression, protein localization and electrophysiology are performed will be required to resolve this issue.

K_IR2.X Channels

Endothelial cells also express inward rectifier K⁺ (K_IR) channels [123]. In resistance arteries and arterioles , endothelial cells appear to express two to four isoforms of K_IR channels: strong inward rectifiers, K_IR2.1, K_IR2.2, and K_IR2.3 (Table 1.1) and weak inward rectifiers K_IR6.1 and K_IR6.2 that form ATP-sensitive K⁺ (K_ATP) channels. The function of K_ATP channels will not be addressed. In general, K_IR channels are tetramers of K_IR subunits, with each subunit having two membrane-spanning domains with a pore-forming loop in between [68]. As shown in Fig. 1.6, at potentials more negative than the K⁺ equilibrium potential, K_IR channels have a higher conductance and pass current in the inward direction, whereas at more positive potentials, channel conductance is reduced. This inward-rectification gives K_IR channels their name and results from voltage-dependent block of the channel pore by intracellular Mg²⁺ and polyamines [68]. The physiological function of K_IR channels is predominantly mediated by the outward “hump” in the current-voltage relationship (Fig. 1.6). Over membrane potentials that accompany this portion of the current-voltage relationship for K_IR, outward currents through these channels will tend to hyperpolarize cells, driving the membrane potential towards the K⁺ equilibrium potential. It is this characteristic of the strong inward rectifiers like K_IR2.1 and 2.2 that sets the resting membrane potential of cardiac muscle, skeletal muscle and nerves to be quite negative and near the K⁺ equilibrium potential [68]. Elevation of extracellular K⁺ increases the conductance of K_IR channels (Fig. 1.6) and shifts the outward hump to more positive membrane potentials which allows these channels to transduce changes in extracellular K⁺ concentration into hyperpolarizing outward K⁺ currents (more on this below). The strong inward rectifier K_IR channels can be blocked by micromolar concentration of Ba²⁺ (Table 1.1), which has been the primary pharmacological tool used to study the physiological function of these channels.

In cultured endothelial cells, currents through strong inward rectifier K_IR channels dominate the whole-cell, current-voltage relationship [3, 123], and from studies of cultured macrovascular and microvascular endothelial cells it was proposed that macrovascular, but not microvascular endothelial cells express K_IR channels [123]. However, studies of freshly isolated endothelial cells from porcine brain capillaries [74], guinea pig coronary capillaries [169], rat mesenteric resistance arteries [28], rat cerebral resistance arteries [86], mouse cerebral penetrating arterioles [101] and hamster cremaster arterioles [81] (Fig. 1.6) all display Ba²⁺-sensitive K_IR currents . Expression of message for K_IR2.1, 2.2 and possibly 2.3 has been reported in guinea pig coronary capillary endothelial cells [99]. Similarly, in primary cultures of rat brain capillary endothelial cells K_IR2.1, 2.2 and a much lower level of K_IR2.3 have been detected [115]. In mouse and rat skeletal muscle arteriolar endothelial cells, we have detected the expression of K_IR2.1, but not K_IR2.2 at the protein level (Fig. 1.7).

The function of K_IR2.X channels in endothelial cells of resistance arteries has been understudied. Theoretically, the expression of these channels in endothelial cells could serve to amplify endothelial cell hyperpolarization induced by the activation of other K⁺ channels and also serve to transduce small increases in extracellular K⁺ into cell hyperpolarization. In blood vessels where K_IR2.X channels are expressed in the vascular smooth muscle, evidence for both of these functions has been demonstrated: smooth muscle K_IR channels serve to amplify smooth muscle hyperpolarization induced by other means [82, 146] and it is well established that elevated extracellular K⁺ causes vasodilatation that is mediated, at least in part, by activation of smooth muscle K_IR2.X channels [85, 101, 122, 186]. It has been argued that endothelial K_IR channels do not play similar roles, primarily based on studies of rat mesenteric arteries in which the endothelial cells, but not the smooth muscle cells express functional K_IR channels [146]. However, this hypothesis has not been adequately tested, particularly in arterioles with only a single layer of smooth muscle and strong expression of K_IR channels. Endothelial and smooth muscle-selective knockdown, as proposed by Longden and Nelson [101], would provide an appropriate system in which to better evaluate the roles played by endothelial K_IR channels.

Concluding Remarks

Endothelial cells importantly contribute to the regulation of the vasomotor function of resistance arteries and arterioles, and it is clear that a number of ion channels in these cells contribute to this function. As noted throughout this chapter, there appears to be substantial regional and species differences in the expression and function of endothelial cell ion channels that clouds a clear view of the function of individual channels and the interplay among and between specific channels. It appears that many, if not all of these channels exist in macromolecular signaling complexes. This further complicates analysis of the individual roles played by specific channels. While knockout approaches are certainly an important tool in studying the function of specific channels, given these macromolecular complexes, the likelihood of off target effects in disrupting other functions of such complexes is significant, but usually overlooked, and may explain why different answers are achieved using knockout approaches vs. pharmacology. The use of cell-specific conditional knockouts, as well as knockins of dominant negative channels coupled with careful pharmacological approaches may help to resolve the questions that still remain. Because of the inherent heterogeneity of expression and function of ion channels in different vascular beds, the detailed study of individual beds among species and particularly in humans is to be encouraged rather than stifled.

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Acknowledgements

Supported NIH grants RO1-HL32469, RO1-HL086483 and PO1-HL070687.

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Department of Pharmacology and Toxicology, Michigan State University, 1355 Bogue Street, B429 Life Sciences, East Lansing, MI, 48824, USA
William F. Jackson

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William F. Jackson
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Correspondence to William F. Jackson .

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University of Illinois at Chicago, Chicago, Illinois, USA
Irena Levitan, PhD
The University of Tennessee, Memphis, Tennessee, USA
Alex M. Dopico, MD, PhD

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Jackson, W.F. (2016). Endothelial Cell Ion Channel Expression and Function in Arterioles and Resistance Arteries. In: Levitan, PhD, I., Dopico, MD, PhD, A. (eds) Vascular Ion Channels in Physiology and Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-29635-7_1

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DOI: https://doi.org/10.1007/978-3-319-29635-7_1
Published: 07 July 2016
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-29633-3
Online ISBN: 978-3-319-29635-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)

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