Chloride Ions, Vascular Function and Hypertension

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. In this review, we discuss recent findings regarding the role of Cl^- in the regulation of vascular tone and arterial blood pressure and its association with hypertension, with a particular focus on TMEM16A and NKCC1.