Recent Developments in Vascular Endothelial Cell Transient Receptor Potential Channels

Abstract

Abstract-Among the 28 identified and unique mammalian TRP (transient receptor potential) channel isoforms, at least 19 are expressed in vascular endothelial cells. These channels appear to participate in a diverse range of vascular functions, including control of vascular tone, regulation of vascular permeability, mechanosensing, secretion, angiogenesis, endothelial cell proliferation, and endothelial cell apoptosis and death. Malfunction of these channels may result in disorders of the human cardiovascular system. All TRP channels, except for TRPM4 and TRPM5, are cation channels that allow Ca 2ϩ influx. However, there is a daunting diversity in the mode of activation and regulation in each case. Specific TRP channels may be activated by different stimuli such as vasoactive agents, oxidative stress, mechanical stimuli, and heat. TRP channels may then transform these stimuli into changes in the cytosolic Ca 2ϩ , which are eventually coupled to various vascular responses. Evidence has been provided to suggest the involvement of at least the following TRP channels in vascular function: TRPC1, TRPC4, TRPC6, and TRPV1 in the control of vascular permeability; TRPC4, TRPV1, and TRPV4 in the regulation of vascular tone; TRPC4 in hypoxia-induced vascular remodeling; and TRPC3, TRPC4, and TRPM2 in oxidative stress-induced responses. However, in spite of the large body of data available, the functional role of many endothelial TRP channels is still poorly understood. Elucidating the mechanisms regulating the different endothelial TRP channels, and the associated development of drugs selectively to target the different isoforms, as a means to treat cardiovascular disease should, therefore, be a high priority. (Circ Res. 2005;97:853-863.)

Low intravascular pressure activates endothelial cell TRPV4 channels, local Ca 2+ events, and IK Ca channels, reducing arteriolar tone

“…ECs contain a range of different TRP channels (21), and in resistance arteries, TRPV4 channels are intimately involved in vasodilation to EC-dependent agonists (22,23) and shear stress-induced dilation (24). Sustained activation to low pressure is a unique addition to this list.…”

Multiple Roles of Protein Kinase A in Arachidonic Acid–Mediated Ca2+ Entry and Tumor-Derived Human Endothelial Cell Migration

“…In addition, it is worth noting that a number of different endothelial calcium-permeable channels are substrates for PKA phosphorylation, including some members of the transient receptor potential (TRP) superfamily of proteins. Interestingly, some of them (including TRPV1 and TRPV4) are also regulated by AA and its metabolites, as well as by NO through S-nitrosylation (23)(24)(25)(26).…”

Phosphorylation of TRPC6 Channels at Thr69 Is Required for Anti-hypertrophic Effects of Phosphodiesterase 5 Inhibition

“…A partial depolarization of plasma membrane by receptor stimulation is reported to increase the frequency of Ca 2ϩ oscillations, leading to activation of nuclear factor of activated T cells (NFAT), a transcription factor that is predominantly regulated by calcineurin (10). Recent reports have indicated that transient receptor potential canonical (TRPC) subfamily proteins play an essential role in agonistinduced membrane depolarization (11,12). The relevance of TRPC channels to pathological hypertrophy is underscored by the observations that heart-targeted transgenic mice expressing TRPC channels caused hypertrophy (13,14) and that TRPC proteins were up-regulated in hypertrophied and failing hearts (14 -17).…”