Transient receptor potential channel activation and endothelium-dependent dilation in the systemic circulation - PubMed (original) (raw)

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Transient receptor potential channel activation and endothelium-dependent dilation in the systemic circulation

David X Zhang et al. J Cardiovasc Pharmacol. 2011 Feb.

Abstract

The endothelium plays a crucial role in the regulation of vascular tone by releasing a number of vasodilator mediators, including nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor(s). The production of these mediators is typically initiated by an increase in intracellular Ca(2+) concentration ([Ca(2+)]i) in endothelial cells. An essential component of this Ca(2+) signal is the entry of Ca(2+) from the extracellular space through plasma membrane Ca(2+)-permeable channels. Although the molecular identification of the potential Ca(2+) entry channel(s) responsible for the release of endothelial relaxing factors is still evolving, accumulating evidence indicates that the transient receptor potential (TRP) channels, a superfamily of Ca(2+)-permeable cation channels, serve as an important mechanism of Ca(2+) entry in endothelial cells and other nonexcitable cells. The activation of these channels has been implicated in diverse endothelial functions ranging from control of vascular tone and regulation of vascular permeability to angiogenesis and vascular remodeling. This review summarizes recent evidence concerning TRP channels and endothelium-dependent dilation in several systemic vascular beds. In particular, we highlight the emerging roles of several TRP channels from the canonical and vanilloid subfamilies, including TRPV4, TRPC4, and TRPC6, in vasodilatory responses to shear stress and receptor agonists and discuss potential signaling mechanisms linking the TRP channel activation and the initiation of endothelium-derived hyperpolarizing factor-mediated responses in endothelial cells.

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Conflict of interest statement

Conflicts of interest None

Figures

Figure 1

Figure 1

Proposed roles for endothelial transient receptor potential (TRP) channels in the activation of endothelium-derived hyperpolarizing factor (EDHF) pathways in response to shear stress and receptor agonists. In endothelial cells, shear stress or receptor agonists (e.g. bradykinin and acetylcholine), by acting on a potential mechanosensor or corresponding receptors respectively, stimulate PLA2 and PLC and subsequently cause the release of intermediate signaling molecules such as AA and its derivatives, and IP3. These mediators then activate several signaling pathways as follows. (1) EETs (CYP metabolites of AA) may activate plasma membrane TRP channels to induce Ca2+ entry from the extracellular space, (2) whereas IP3 causes Ca2+ release from intracellular IP3-sensitive stores. A subsequent elevation in endothelial [Ca2+]i, consisting of this Ca2+ release (initial transient) followed by the Ca2+ entry (plateau phase), may activate endothelial IKCa/SKCa channels resulting in membrane hyperpolarization in endothelial cells. This hyperpolarization may be further transmitted to underlying smooth muscle cells, leading to smooth muscle hyperpolarization and relaxation. (3) Endothelial EETs also function themselves as diffusible EDHF factors to directly hyperpolarize and relax smooth muscle cells. Plausible parallel/alternative TRP channel-associated signaling events (marked in light colored arrows) may also occur in endothelial cells. These include the activation of TRP channels by other potential mechanisms such as shear stress itself (4) or Ca2+-store depletion (5), regulation of TRP channel activity by endothelial membrane hyperpolarization as the result of IKCa/SKCa opening (6), and stimulation of PLA2 by TRP channel-mediated Ca2+ entry (7). Ach, acetylcholine; AA, arachidonic acid; BK, bradykinin; CYP, cytochrome P450; EETs, epoxyeicosatrienoic acids; ER, endoplasmic reticulum; IP3, inositol 1,4,5-triphosphate; I/SKCa, intermediate/small conductance Ca2+-activated K+ channel; PLA2, phospholipase A2; PLC, phospholipase C.

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