Endothelium-Dependent Hyperpolarization (EDH) in Hypertension: The Role of Endothelial Ion Channels

Abstract

Upon stimulation with agonists and shear stress, the vascular endothelium of different vessels selectively releases several vasodilator factors such as nitric oxide and prostacyclin. In addition, vascular endothelial cells of many vessels regulate the contractility of the vascular smooth muscle cells through the generation of endothelium-dependent hyperpolarization (EDH). There is a general consensus that the opening of small- and intermediate-conductance Ca²⁺-activated K⁺ channels (SK_Ca and IK_Ca) is the initial mechanistic step for the generation of EDH. In animal models and humans, EDH and EDH-mediated relaxations are impaired during hypertension, and anti-hypertensive treatments restore such impairments. However, the underlying mechanisms of reduced EDH and its improvement by lowering blood pressure are poorly understood. Emerging evidence suggests that alterations of endothelial ion channels such as SK_Ca channels, inward rectifier K⁺ channels, Ca²⁺-activated Cl^- channels, and transient receptor potential vanilloid type 4 channels contribute to the impaired EDH during hypertension. In this review, we attempt to summarize the accumulating evidence regarding the pathophysiological role of endothelial ion channels, focusing on their relationship with EDH during hypertension.

Keywords: Ca2+-activated Cl− channel; Ca2+-activated K+ channel; endothelial function; endothelium-dependent hyperpolarization; endothelium-derived hyperpolarizing factor; hypertension; transient receptor potential vanilloid type 4 channel.

Figure 1

Diffusible and contact-mediated mechanisms of endothelium-dependent smooth muscle hyperpolarization. In certain vascular beds in specific conditions, diffusible factors such as epoxyeicosatrienoic acids (EETs), K⁺ ions, and hydrogen peroxide (H₂O₂) hyperpolarize smooth muscle cells through the opening of potassium channels and/or Na⁺/K⁺-ATPase. In addition, endothelium-dependent hyperpolarization initiated in endothelial cells with a rise in intracellular calcium and the subsequent activation of small (SK_Ca) and intermediate conductance (IK_Ca) Ca²⁺-activated K⁺ channels spreads to adjacent smooth muscle cells via myoendothelial gap junctions (MEGJs) in a number of vascular beds. In some vascular beds, combination of diffusible and contact-mediated mechanisms underpin smooth muscle hyperpolarization.

Figure 2

Downregulation of transient receptor potential vanilloid type 4 channel (TRPV4) in hypertension. Representative tracing of GSK1016790A (GSK), a selective TRPV4 activator, induced hyperpolarization (A) and relaxation (B) in mesenteric arteries of Wistar–Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP). GSK evoked hyperpolarization and relaxation in WKY but not in SHRSP arteries. Arteries were depolarized (A) or pre-contracted (B) with phenylephrine (10⁻⁵ mol/L). Indomethacin (10⁻⁵ mol/L) and N^ω-nitro-l-arginine (l-NAME, 10⁻⁴ mol/L) were present throughout the experiments. (C) Representative immunoblots of the expression of TRPV4 in mesenteric arteries from WKY and SHRSP. The expression of the TRPV4 protein was significantly decreased in the SHRSP mesenteric arteries compared with that from WKY. Modified from Seki et al. [46].

Figure 3

Endothelial ion channels in normotension and hypertension. In normotension, in response to agonist stimulation of endothelial cells, a rise in intracellular Ca²⁺ occurs due to the release from intracellular Ca²⁺ stores and Ca²⁺ entry via transient potential vanilloid type 4 channel (TRPV4). A rise in intracellular Ca²⁺ subsequently generates endothelium-dependent hyperpolarization (EDH) through the activation of both small (SK_Ca) and intermediate conductance (IK_Ca) Ca²⁺-activated K⁺ channels. In some arteries, K⁺ released from endothelial K_Ca channels activates endothelial Kir channels, which in turn amplifies EDH. EDH spreads to adjacent smooth muscle cells via myoendothelial gap junctions (MEGJs), resulting in vascular relaxation. In hypertension, alterations of endothelial ion channels additively reduce EDH; these alterations include downregulation of endothelial SK_Ca and TRPV4 channels, upregulation of endothelial Ca²⁺-activated chloride channels (CaCCs), and functional loss of endothelial Kir channels.