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Blood pressure is determined by cardiac output and systemic vascular resistance, and mediators that induce vasoconstriction will increase systemic vascular resistance and thus elevate blood pressure. While peripheral vascular resistance reflects a complex interaction of multiple factors, vascular ion channels and transporters play important roles in the regulation of vascular tone by modulating the membrane potential of vascular cells. In vascular smooth muscle cells, chloride ions (Cl−) are a type of anions accumulated by anion exchangers and the anion–proton cotransporter system, and efflux of Cl− through Cl− channels depolarizes the membrane and thereby triggers vasoconstriction. Among these Cl− regulatory pathways, emerging evidence suggests that upregulation of the Ca2+-activated Cl− channel TMEM16A in the vasculature contributes to the increased vascular contractility and elevated blood pressure in hypertension. A robust accumulation of intracellular Cl− in vascular smooth muscle cells through the increased activity of Na+–K+–2Cl− cotransporter 1 (NKCC1) during hypertension has also been reported. Thus, the enhanced activity of both TMEM16A and NKCC1 could act additively and sequentially to increase vascular contractility and hence blood pressure in hypertension.
- chloride
- calcium-activated chloride channel
- hypertension
- Na+–K+–2Cl− Cotransporter1
1. Ca2+-Activated Chloride Channels (CaCCs) in Vascular Smooth Muscle Cells
It is generally accepted that essential hypertension is characterized by an increased peripheral resistance [49,50]. The increased peripheral resistance in hypertension is determined by an integral and complex interplay between various pathogenic factors, including increased sympathetic nervous activity, enhanced calcium ion mobilization in vascular smooth muscle cells, increased calcium sensitivity of vascular smooth muscle cells and reduced production of endothelium-derived relaxing factors, to name a few [50,51]. Among these factors, alterations in the function of vascular ion channels during hypertension contribute to the increased peripheral resistance by shifting the membrane potential to depolarized levels [22,50,52].
Emerging evidence reveals an upregulation of expression and/or function of CaCCs in vascular smooth muscle cells of spontaneous hypertensive rats (SHRs), a genetic model of human essential hypertension. Wang et al. for the first time revealed that TMEM16A is the molecular counterpart for the increased activity of CaCCs in vascular smooth muscle cells of SHRs, and that TMEM16A protein expression is significantly upregulated in the aorta, the carotid arteries, the hindlimb arteries and the mesenteric arteries of SHRs compared to those of normotensive Wistar Kyoto (WKY) rats [56]. Consistent with the seminal findings of Wang and colleagues [56], the increased TMEM16A expression levels and the resultant potentiation of vasoconstrictions have also been reported in smooth muscle cells of the coronary arteries [57] and the renal arterioles [47] of SHRs.
Importantly, the increased expression and function of TMEM16A appear to be associated with blood pressure elevation in SHRs: the in vivo knockdown of TMEM16A by small interfering RNA (siRNA) transfection prevented blood pressure rise, and the in vivo inhibition of TMEM16A activity by T16Ainh-A01, a TMEM16A inhibitor, reduced blood pressure in SHRs [56]. Similarly, a recent study in SHRs showed that in vitro treatment of mesenteric resistance arteries with TMinh-23, a small molecule inhibitor of vascular smooth muscle TMEM16A, blocked vascular smooth muscle constriction in response to vasoconstrictor stimuli, and in vivo treatment with TMinh-23 reduced blood pressure in SHRs with minimal blood pressure change in normotensive rats and mice [58]. Together, these findings implicate vascular smooth muscle CaCC TMEM16A as a possible contributor in the pathogenesis of hypertension in SHRs.
2. Ca2+-Activated Chloride Channels (CaCCs) in Vascular Endothelial Cells
In addition to their expression in vascular smooth muscle cells, CaCCs have been reported to be present in some vascular endothelial cells [81,82,83,84]. Although the physiological role of endothelial CaCCs is still not well understood, the endothelial CaCCs may contribute to the regulation of the resting membrane potential of the endothelial cells. Indeed, in mouse brain capillary endothelial cells, pharmacological blockade or knockdown of TMEM16A with siRNA induced membrane hyperpolarization, suggesting that the activation of endothelial CaCCs acts to depolarize the membrane potential of the endothelial cells [83]. Further support for this notion comes from the study by Yamamoto et al. [85]. They found that, in the isolated endothelium of guinea pig mesenteric arteries, ACh increased the intracellular concentration of Ca2+, which subsequently activated endothelial small conductance Ca2+-activated K+ channels (SKCas), intermediate conductance KCa (IKCa) and CaCC simultaneously, and the endothelium-dependent hyperpolarization (EDH) through the activation of both SKCa and IKCa was counteracted by the opposing membrane depolarization evoked by the activation of CaCCs [85].
With respect to the alteration of endothelial CaCCs in hypertension, we have previously shown a functional upregulation of endothelial CaCCs in mesenteric resistance arteries of SHRs [86]. In that study, after blockade of EDH with KCa channel inhibitors, iontophoresed acetylcholine (ACh) evoked a rapid and substantial membrane depolarization in mesenteric resistance arteries of SHRs, but only negligible slow depolarization was detected in those of WKY rats [86,87]. Moreover, the inhibition of the ACh-evoked depolarization by CaCC inhibitors improved the impaired ACh-induced EDH in mesenteric arteries of SHRs, suggesting that an increased activity of endothelial CaCCs may be responsible for the impairment of EDH.
A negative causal link between the activity of endothelial CaCCs, specifically TMEM16A, and endothelial function has also been reported in other studies [82,84]. Thus, in Ang II-induced hypertensive mice, in which the expression of vascular endothelial TMEM16A is increased, the endothelial-specific TMEM16A knockout ameliorated endothelial function and lowered the systolic blood pressure, whereas the endothelial-specific TMEM16A overexpression deteriorated endothelial function and further elevated the systolic blood pressure [82], and these interactions appear to be related to the facilitating effects of TMEM16A on reactive oxygen species generation via Nox2-containing NADPH oxidase [82]. Another study showed that overexpression of TMEM16A in human pulmonary endothelial cells led to a decrease in ACh-induced NO production [84]. Taken together, these findings suggest that upregulation of endothelial CaCC TMEM16A may contribute to the impaired endothelial function, and if so, that it likely does so via a reduction in the activity of EDH and/or NO; finally, the results suggest that such a reduction in EDH and/or NO activity may be at least partly responsible for the elevated blood pressure in hypertension.
3. Na+–K+–2Cl− Cotransporter1 (NKCC1)
NKCC1 located on vascular smooth muscle cells functions to accumulate intracellular Cl− [20,21]. The most compelling evidence of the functional role of NKCC1 in the regulation of vascular tone and arterial blood pressure comes from studies on NKCC1 knockout mice: the systolic blood pressure was significantly reduced in NKCC1 knockout mice compared to wild-type mice [94], and treatment with bumetanide, an inhibitor of NKCC1 [95], inhibited the vascular contractile activity and lowered mean arterial blood pressure in wild-type mice, with the effects being lost in NKCC1 knockout mice [94,96]. Thus, theoretically, an increase in the activity of the vascular smooth muscle NKCC1 could augment vascular contractility and subsequently lead to enhanced blood pressure, and this is indeed the case in several types of hypertensive rats.
In some experimental models of hypertensive rats, including SHRs [97,98,99], Milan hypertensive rats [100] and deoxycorticosterone acetate (DOCA) salt hypertensive rats [101], increase in the activity of NKCC in vascular smooth muscle cells has been reported. The increase in the intracellular Cl− concentration because of the increase in the activity of NKCC1 would increase the driving force for Cl− efflux via Cl− channels such as CaCCs upon vasoconstrictor stimulation, and the increase in Cl− efflux would make the membrane potential more depolarized [20], which in turn would enhance the open probability of voltage-gated L-type Ca2+ channels, leading to an increase in vascular tone. Since, as discussed in the previous section, CaCCs are also functionally upregulated in the vasculature of hypertensive rats, we propose that the enhanced activities of NKCC1 and CaCCs act additively and sequentially to increase vascular contractility and hence blood pressure in hypertension.
Further exploration of the arterial tone regulation by Cl− may facilitate a better understanding of the pathogenesis of hypertension, which may help to develop a novel therapeutic strategy to tackle hypertension and hypertension-associated cardiovascular diseases.
This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10092316
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