Ion Channels and Their Functional Role in Vascular Endothelium

Abstract

Endothelial cells (EC) form a unique signal-transducing surface in the vascular system. The abundance of ion channels in the plasma membrane of these nonexcitable cells has raised questions about their functional role. This review presents evidence for the involvement of ion channels in endothelial cell functions controlled by intracellular Ca(2+) signals, such as the production and release of many vasoactive factors, e.g., nitric oxide and PGI(2). In addition, ion channels may be involved in the regulation of the traffic of macromolecules by endocytosis, transcytosis, the biosynthetic-secretory pathway, and exocytosis, e.g., tissue factor pathway inhibitor, von Willebrand factor, and tissue plasminogen activator. Ion channels are also involved in controlling intercellular permeability, EC proliferation, and angiogenesis. These functions are supported or triggered via ion channels, which either provide Ca(2+)-entry pathways or stabilize the driving force for Ca(2+) influx through these pathways. These Ca(2+)-entry pathways comprise agonist-activated nonselective Ca(2+)-permeable cation channels, cyclic nucleotide-activated nonselective cation channels, and store-operated Ca(2+) channels or capacitative Ca(2+) entry. At least some of these channels appear to be expressed by genes of the trp family. The driving force for Ca(2+) entry is mainly controlled by large-conductance Ca(2+)-dependent BK(Ca) channels (slo), inwardly rectifying K(+) channels (Kir2.1), and at least two types of Cl( -) channels, i.e., the Ca(2+)-activated Cl(-) channel and the housekeeping, volume-regulated anion channel (VRAC). In addition to their essential function in Ca(2+) signaling, VRAC channels are multifunctional, operate as a transport pathway for amino acids and organic osmolytes, and are possibly involved in endothelial cell proliferation and angiogenesis. Finally, we have also highlighted the role of ion channels as mechanosensors in EC. Plasmalemmal ion channels may signal rapid changes in hemodynamic forces, such as shear stress and biaxial tensile stress, but also changes in cell shape and cell volume to the cytoskeleton and the intracellular machinery for metabolite traffic and gene expression.

Depolarization‐induced calcium influx in rat mesenteric small arterioles is mediated exclusively via mibefradil‐sensitive calcium channels

“…However, based on our Ca 2 þ response data, we cannot exclude that the endothelial cells might also express mibefradil-sensitive Ca 2 þ channels. The current view is that endothelial cells do not express voltagedependent Ca 2 þ channels (Domenighetti et al, 1998;Nilius & Droogmans, 2001), although the opposite has also been suggested (Vinet & Vargas, 1999;Wu et al, 2003).…”

Enhanced spontaneous Ca2+ events in endothelial cells reflect signalling through myoendothelial gap junctions in pressurized mesenteric arteries

“…Endothelial cell Ca 2+ has a crucial role in controlling vascular tone and homeostasis by releasing nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF) [1][2][3][4][5][6] and affecting gene expression, angiogenesis, cell growth, and leukocyte migration [7,8], respectively. The level of cytoplasmic [Ca 2+ ] i can be modulated not only by the direct action of agonists and haemodynamic forces on the endothelial cells, but also indirectly by communication from surrounding cells.…”

Hydrogen peroxide stimulates the Ca2+-activated big-conductance K channels (BK) through cGMP signaling pathway in cultured human endothelial cells

“…Ca 2+ -activated K channels including small-conductance, intermediate-conductance and bigconductance have been shown to be expressed in endothelial cells [1][2][3][4][5]. Although Ca 2+ -activated small conductance and intermediate-conductance K channels are mainly responsible for determining the membrane potential under basal conditions [3], BK channels may also be involved in regulating the membrane potential of endothelial cells because BK channels have a high channel conductance.…”

“…Although Ca 2+ -activated small conductance and intermediate-conductance K channels are mainly responsible for determining the membrane potential under basal conditions [3], BK channels may also be involved in regulating the membrane potential of endothelial cells because BK channels have a high channel conductance. It is conceivable that BK channels could play an important role in participating in generating the membrane potential in endothelial cells when they are activated [3]. Indeed, it has been shown that expression of BK channels in cultured endothelial cells caused a transient hyperpolarization induced by ATP [2].…”

“…Indeed, it has been shown that expression of BK channels in cultured endothelial cells caused a transient hyperpolarization induced by ATP [2]. The membrane potential of endothelial cells plays an important role in regulating Ca 2+ influx via Ca 2+ -permeable channels such that hyperpolarization is expected to increase electrochemical driving force of Ca 2+ entry in endothelial cells [3]. Thus, activation of BK channels are expected to elevate intracellular Ca 2+ which further enhances the release of endothelial-derived relaxing factor (EDRF) including nitric oxide (NO) and epoxyeicosatrienoic acid (EET) in endothelial cells [6].…”