**5. KV channel in VSMCs**

KV channels comprise a large family of channels that are expressed in both excitable and nonexcitable cells. In excitable cells, such as neurons or cardiac myocytes, the control of the resting membrane potential (resting Em) and frequency and duration of action potentials depend on KV channels. In nonexcitable tissues, these channels are involved in various processes ranging from secretion to cell proliferation [75]. In humans, KV channels are encoded by 40 genes, and each Kv channel gene encodes a single protein; functional Kv channels are divided into 12 subfamilies (KV1–KV12). All mammalian KV channels consist of four α-subunits and six transmembrane α-helical segments (S1–S6), and a membrane-reentering P-loop forms each α-subunit. This ion conduction pore is lined by four S5–P–S6 sequences. The four S1–S4 segments, each containing four positively charged arginine residues in the S4 helix, act as voltage sensor domains and "gate" the pore by "pulling" on the S4–S5 linker [76, 77]. The large number of KV channel genes combined with the possibility of heterotetramerization creates a large functional diversity of KV currents. This diversity is increased by the interactions of these channels with accessory proteins that are capable of modulating the gating properties and assist in trafficking and multimerization [75]. Since the KV channel subunits form homo and heterotetramers, the biophysical properties, physiological regulatory mechanisms, and pharmacological properties of these channels vary. Although the KV1.1–1.6 mRNAs have been detected in rat cerebral arteries, only the KV1.2 and 1.5 proteins were detected, suggesting that in the cerebral vasculature, the functional KV channel is a KV1.2/1.5 heterotetramer. Members of the KV1 and KV2 family are postulated to be the predominant Kv channels that regulate arterial tone (**Table 1**) [78, 79].

KV channels regulate membrane potential. Numerous studies have been conducted to explore the mechanisms by which these channels affect vascular tone in subjects with hypertension. Under Ca2+-replete conditions, KV currents in arterial SMCs from hypertensive animals are altered. KV1.2 is expressed at higher levels, whereas KV1.5 is expressed at the same levels in SMCs from hypertensive animals


#### **Table 1.**

*The three family members of K+ channels.*

than in cells from normal animals [80]. Li et al. confirmed the effect of exercise training on alterations in KV expression in thoracic aorta smooth muscle cells from spontaneously hypertensive rats (SHR). Rats were divided into three groups, a sedentary spontaneously hypertensive group (SHR-SED) and an exercise training spontaneously hypertensive group (SHR-EX), along with age-matched Wistar-Kyoto rats (WKYs) as the control group. Significantly, lower levels of the KV1.2 and KV1.5 channels were detected in the SHR-SED group than in the WKY group, while this decrease was inhibited in the SHR-EX group. Exercise training reverses the pathological expression of the KV1.2 and KV1.5 channels in aortic myocytes from SHRs, and thus is one of the favorable effects of exercise training on large conduit arteries [81].

The KV1.5 protein is present in the vascular smooth muscle layer of both porcine and human coronary arteries, including microvessels [82]. The mean arterial pressure (MAP), myocardial blood flow (MBF), and ejection fraction (EF) have been measured in wild-type (WT) mice, mice null for KV1.5 channels (KV1.5<sup>−</sup>/<sup>−</sup>), and mice with inducible, smooth muscle-specific expression of KV1.5 channels (on KV1.5<sup>−</sup>/<sup>−</sup> and wild type backgrounds). During a norepinephrine (NE) infusion, significantly lower values for EF and MSF were observed in KV1.5<sup>−</sup>/<sup>−</sup> mice than in WT mice. The expression of KV1.5 channels in smooth muscle in mice

**37**

ZKX16048).

**Conflicts of interest**

*Potassium Channels in the Vascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.82474*

might contribute to vascular dysfunction [86].

**6. Conclusions and further perspective**

ing vascular tone and tissue perfusion. Dysfunctional K+

The authors have no conflict of interest to declare.

homeostasis through heterogeneous and complex mechanisms. K+

edge of the expression of K+

still deserve to study. How these K+

**Acknowledgements/funding**

tion and tissue hypoxia [83].

on the null background rescued this phenotype of impaired metabolic dilation, indicating that Kv1.5 channels in vascular smooth muscle play a critical role in coupling myocardial blood flow to cardiac metabolism. The absence of these channels disassociates metabolism from flow, resulting in cardiac pump dysfunc-

In addition to the KV1 family, the KV7 (KV7.4 and KV7.5) family has recently been shown to be a major determinant of vascular tone. KV7 is expressed at similar levels in the murine aorta, carotid, femoral, and mesenteric artery, whereas the expression of KV7.4 and KV7.5 is greater than or equal to KV7.1 [84]. By activating KV7.4 channels, the application of 4-aminopyridine (4-AP) to noradrenalinepreconstricted rat mesenteric arteries contributes to the relaxation of the vessel [85]. The interaction between microRNAs (miRs) and KV7.4 is also important in the vasculature. The expression of miR153 is increased in mesenteric, renal, and thoracic aortic arteries from SHRs compared to NT rats. In SHRs, the expression of KV7.4 is decreased, whereas this change is not consistently associated with a change in transcript level because a difference in mRNA levels was not observed in renal and mesenteric arteries between SHRs and normotensive (NT) rats. In a study using synthetic RNA molecules, miR153 repressed the translation of KV7.4 mRNA rather than degrading the transcript. Thus, miRs regulate the expression of Kv7.4 in the vasculature, and this post-transcriptional regulatory pathway

Studies performed over several decades have substantially improved our knowl-

for gene therapy for hypertension. The BK β1 subunit, KV 1.5, KV 7.4, and some other genes should be studied as gene therapy targets. However, some remaining questions

This study was supported by the National Natural Science Foundation of China (81370304); Natural Science Foundation of Jiangsu Province (BK20151085); Jiangsu Provincial Key Research and Development Program (BE2018611); the 10th Summit of Six Top Talents of Jiangsu Province (2016-WSN-185); Medical Science and technology development Foundation of Nanjing Department of Health (YKK15101,

design better drugs to target these channels with some degree of specificity?

channels in the vascular system and their roles in regulat-

channels work in microvasculature? How can we

channels can alter vascular

channels are targets

*Potassium Channels in the Vascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.82474*

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

Ca2+-activated K+ channels (Kca)

ATP-sensitive K+ channels (KATP)

Voltage-gated K+ channels (KV)

**Table 1.**

*The three family members of K+*

**Family Subtype in vascular Gene name Inhibitor**

KCa1(BKCa) KCNMA1

KCNMB1-4

KCa3(IKCa) KCNN4 Charybdotoxin

Kir6.1 KCNJ8 Glibenclamide

Kir6.2 KCNJ11 Tolbutamide

Kv7 KCNQ TEA

Kv1 KCNA 4-Aminopyridine(4-AP)

Kv2 KCNB 4-Aminopyridine(4-AP)

KCa2(SKCa) KCNN1-3 Apamin

Iberiotoxin (IBTX) Charybdotoxin Paxilline

UCL1684 TRAM-34 Psora-4

Clotrimazole TRAM-34 NS6180 Psora-4

Tolbutamide

Glibenclamide ML133

(TEA) Correolide α-Dendrotoxin

(TEA) Ba2+ SsmTx-1

Linopirdine XE991 Chromanol 293B

Tetraethylammonium

Tetraethylammonium

than in cells from normal animals [80]. Li et al. confirmed the effect of exercise training on alterations in KV expression in thoracic aorta smooth muscle cells from spontaneously hypertensive rats (SHR). Rats were divided into three groups, a sedentary spontaneously hypertensive group (SHR-SED) and an exercise training spontaneously hypertensive group (SHR-EX), along with age-matched Wistar-Kyoto rats (WKYs) as the control group. Significantly, lower levels of the KV1.2 and KV1.5 channels were detected in the SHR-SED group than in the WKY group, while this decrease was inhibited in the SHR-EX group. Exercise training reverses the pathological expression of the KV1.2 and KV1.5 channels in aortic myocytes from SHRs, and thus is one of the favorable effects of exercise training on large conduit arteries [81]. The KV1.5 protein is present in the vascular smooth muscle layer of both porcine and human coronary arteries, including microvessels [82]. The mean arterial pressure (MAP), myocardial blood flow (MBF), and ejection fraction (EF) have been measured in wild-type (WT) mice, mice null for KV1.5 channels (KV1.5<sup>−</sup>/<sup>−</sup>), and mice with inducible, smooth muscle-specific expression of KV1.5 channels (on KV1.5<sup>−</sup>/<sup>−</sup> and wild type backgrounds). During a norepinephrine (NE) infusion, significantly lower values for EF and MSF were observed in KV1.5<sup>−</sup>/<sup>−</sup> mice than in WT mice. The expression of KV1.5 channels in smooth muscle in mice

 *channels.*

**36**

on the null background rescued this phenotype of impaired metabolic dilation, indicating that Kv1.5 channels in vascular smooth muscle play a critical role in coupling myocardial blood flow to cardiac metabolism. The absence of these channels disassociates metabolism from flow, resulting in cardiac pump dysfunction and tissue hypoxia [83].

In addition to the KV1 family, the KV7 (KV7.4 and KV7.5) family has recently been shown to be a major determinant of vascular tone. KV7 is expressed at similar levels in the murine aorta, carotid, femoral, and mesenteric artery, whereas the expression of KV7.4 and KV7.5 is greater than or equal to KV7.1 [84]. By activating KV7.4 channels, the application of 4-aminopyridine (4-AP) to noradrenalinepreconstricted rat mesenteric arteries contributes to the relaxation of the vessel [85]. The interaction between microRNAs (miRs) and KV7.4 is also important in the vasculature. The expression of miR153 is increased in mesenteric, renal, and thoracic aortic arteries from SHRs compared to NT rats. In SHRs, the expression of KV7.4 is decreased, whereas this change is not consistently associated with a change in transcript level because a difference in mRNA levels was not observed in renal and mesenteric arteries between SHRs and normotensive (NT) rats. In a study using synthetic RNA molecules, miR153 repressed the translation of KV7.4 mRNA rather than degrading the transcript. Thus, miRs regulate the expression of Kv7.4 in the vasculature, and this post-transcriptional regulatory pathway might contribute to vascular dysfunction [86].
