The TMEM16A channel as a potential therapeutic target in vascular disease

Abstract

Purpose of review: The transmembrane protein 16A (TMEM16A) Ca 2+ -activated Cl - channel constitutes a key depolarising mechanism in vascular smooth muscle and contractile pericytes, while in endothelial cells the channel is implicated in angiogenesis and in the response to vasoactive stimuli. Here, we offer a critical analysis of recent physiological investigations and consider the potential for targeting TMEM16A channels in vascular disease.

Recent findings: Genetic deletion or pharmacological inhibition of TMEM16A channels in vascular smooth muscle decreases artery tone and lowers systemic blood pressure in rodent models. Inhibition of TMEM16A channels in cerebral cortical pericytes protects against ischemia-induced tissue damage and improves microvascular blood flow in rodent stroke models. In endothelial cells, the TMEM16A channel plays varied roles including modulation of cell division and control of vessel tone through spread of hyperpolarisation to the smooth muscle cells. Genetic studies implicate TMEM16A channels in human disease including systemic and pulmonary hypertension, stroke and Moyamoya disease.

Summary: The TMEM16A channel regulates vascular function by controlling artery tone and capillary diameter as well as vessel formation and histology. Preclinical and clinical investigations are highlighting the potential for therapeutic exploitation of the channel in a range of maladaptive states of the (micro)circulation.

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FIGURE 1

Direction of TMEM16A currents in vascular cells. The direction and magnitude of the TMEM16A current (I_TMEM16A) in vascular cells determine its effect on the cell's membrane potential. In VSMCs, pericytes and some ECs (left panel), opening of TMEM16A channels leads to an efflux of Cl⁻, according to the Cl⁻ electrochemical gradient, and membrane depolarisation. In contrast, in some ECs, such as those of mouse mesenteric arteries, the lower [Cl^–]_i means that the opening of TMEM16A channels will lead to Cl⁻ influx and membrane hyperpolarisation.

FIGURE 2

Roles for TMEM16A in VSMCs, ECs and contractile pericytes. (a) VSMCs and pericytes have a high Cl⁻ concentration [Cl⁻]_i, produced by a series of active transport mechanisms in the plasma membrane (not shown). Agonists acting on G_qPCRs stimulate the inositol tris-phosphate (IP₃) pathway and Ca²⁺ release from the sarcoplasmic reticulum (SR). This initial rise in [Ca²⁺]_i promotes opening of TMEM16A channels, causing Cl⁻ efflux, V_m depolarisation and opening of CaV channels. The resulting further increase in [Ca²⁺]_i leads to cell contraction. Phospholipase C (PLC) activation that follows G_qPCR stimulation, leads to depletion of plasmalemmal phosphatidylinositol 4,5-bisphosphate (PIP₂). PIP₂ is a stimulator of TMEM16A channel activity; thus, PIP₂ depletion provides an antagonizing effect on the activation of the channel that follows IP₃-mediated Ca²⁺ release. TMEM16A activation may also be coupled with Ca²⁺ entry via TRPC6 channels in VSMCs of some vascular beds. In some ECs, such as in mouse mesenteric arteries, acetylcholine (Ach) acting on muscarinic M3 receptors, leads to activation of the TRPV4 channel. The TRPV4-mediated Ca²⁺ entry activates TMEM16A channels leading to Cl⁻ influx; the resulting hyperpolarization can be transmitted through gap junctions to induce VSMCs relaxation. (b) Cerebral contractile pericytes (top panel: diagrammatic representation of a pericyte surrounding the cortical capillary; lower panel: representation of a pericyte soma with processes surrounding the capillary shown in cross section). The TMEM16A channel is activated following G_qPCR stimulation, as in the VSMCs of the upstream arterioles. In ischemia, the reduction in intracellular ATP prevents Ca²⁺ extrusion through the plasma membrane Ca²⁺ ATPase (PMCA). The resulting increase in [Ca²⁺]_i favors pericyte contraction.

FIGURE 3

Pathways involved in epithelial and vascular smooth muscle cell proliferation. TMEM16A channel activity may be involved in the control of cell proliferation. Cholesterol may control the level of TMEM16A expression and suppresses TMEM16A channel activity. Mitochondrial TMEM16A activation may stimulate ROS production which in turn inhibits cell proliferation of ECs and VSMCs in some vascular beds, as detailed in the main text.