On the Role of Endothelial TRPC3 Channels in Endothelial Dysfunction and Cardiovascular Disease (original) (raw)
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TRPC channels: Dysregulation and Ca2+ Mishandling In Ischemic Heart Disease
Transient receptor potential canonical (TRPC) channels are ubiquitously expressed in excitable and non-excitable cardiac cells where they sense and respond to a wide variety of physical and chemical stimuli. As other TRP, TRPC may form homo or heterotetrameric ion channel, and they can associate with other membrane receptors and ion channels to regulate intracellular calcium concentration. Dysfunctions of TRPC channels are involved in many types of cardiovascular diseases. Significant increase of the expression of different TRPC isoforms has been observed in different animal model of heart infarcts, and in vitro experimental model of ischemia and reperfusion. TRPC-mediated increase of the intracellular Ca2+ concentration seems required for the activation of signaling pathway that plays minor roles in the healthy heart, but they are more relevant for cardiac responses to ischemia, such as the activation of different factors of transcription and cardiac hypertrophy, fibrosis, and angi...
Expression of TRPC homologs in endothelial cells and smooth muscle layers of human arteries
Histochemistry and Cell Biology, 2004
TRPC channels are a group of Ca 2+ -permeable nonselective cation channels that mediate store-operated and/or agonist-stimulated Ca 2+ influx in a variety of cell types. In this study, we extensively examined the expression patterns of TRPC homologs in human vascular tissues. RT-PCR amplified cDNA fragments of TRPC1 (505 bp), TRPC3 (372 bp), TRPC4 (499 bp), TRPC5 (325 bp), TRPC6 (509 bp), and TRPC7 (187 bp) from RNA isolated from cultured human coronary artery endothelial cells. In situ hybridization yielded strong labeling of TRPC1,3-6 in the endothelial and smooth muscle cells of human coronary and cerebral arteries. TRPC7 labeling was exclusively found in endothelial cells but not in smooth muscle cells. Results from immunohistochemical staining were consistent with those from in situ hybridization. Similar expression patterns of TRPC homologs were also observed in arterioles and vaso vasora. In conclusion, our study indicates that TRPC homologs are widely expressed in human vessels of all calibers, including medium-sized coronary arteries and cerebral arteries, smaller-sized resistance arteries, and vaso vasora. These results suggest a ubiquitous role of TRPC homologs in regulating blood supply to different regions and in controlling arterial blood pressure.
Proceedings of the National Academy of Sciences of the United States of America, 2015
In previous in vitro studies, we showed that Transient Receptor Potential Canonical 3 (TRPC3), a calcium-permeable, nonselective cation channel endowed with high constitutive function, is an obligatory component of the inflammatory signaling that controls expression of the vascular cell adhesion molecule-1 (VCAM-1) and monocyte adhesion to coronary artery endothelial cells. Also, TRPC3 expression in these cells was found to be up-regulated by proatherogenic factors, which enhanced inflammation and VCAM-1 expression. However, it remained to be determined whether these in vitro findings were of relevance to atherosclerotic lesion development in vivo. To answer this important question in the present work, we generated mice with endothelial-specific overexpression of human TRPC3 in an Apoe knockout background (TgEST3ApoeKO) and examined lesions in the aortic sinus following 10 and 16 wk on a high-fat diet. No significant differences were found in size or complexity of early stage lesion...
TRPC and TRPV Channels’ Role in Vascular Remodeling and Disease
International Journal of Molecular Sciences
Transient receptor potentials (TRPs) are non-selective cation channels that are widely expressed in vascular beds. They contribute to the Ca2+ influx evoked by a wide spectrum of chemical and physical stimuli, both in endothelial and vascular smooth muscle cells. Within the superfamily of TRP channels, different isoforms of TRPC (canonical) and TRPV (vanilloid) have emerged as important regulators of vascular tone and blood flow pressure. Additionally, several lines of evidence derived from animal models, and even from human subjects, highlighted the role of TRPC and TRPV in vascular remodeling and disease. Dysregulation in the function and/or expression of TRPC and TRPV isoforms likely regulates vascular smooth muscle cells switching from a contractile to a synthetic phenotype. This process contributes to the development and progression of vascular disorders, such as systemic and pulmonary arterial hypertension, atherosclerosis and restenosis. In this review, we provide an overview...
Elucidation of a TRPC6-TRPC5 Channel Cascade That Restricts Endothelial Cell Movement
Molecular Biology of The Cell, 2008
Canonical transient receptor potential (TRPC) channels are opened by classical signal transduction events initiated by receptor activation or depletion of intracellular calcium stores. Here, we report a novel mechanism for opening TRPC channels in which TRPC6 activation initiates a cascade resulting in TRPC5 translocation.
TRP channels in endothelial function and dysfunction
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2007
Endothelial cells produce various factors that regulate vascular tone, vascular permeability, angiogenesis, and inflammatory responses. The dysfunction of endothelial cells is believed to be the major culprit in various cardiovascular diseases, including hypertension, atherosclerosis, heart and renal failure, coronary syndrome, thrombosis, and diabetes. Endothelial cells express multiple transient receptor potential (TRP) channel isoforms, the activity of which serves to modulate cytosolic Ca 2+ levels ([Ca 2+ ] i ) and regulate membrane potential, both of which affect various physiological processes. The malfunction and dysregulation of TRP channels is associated with endothelial dysfunction, which is reflected by decreased nitric oxide (NO) bioavailability, inappropriate regulation of vascular smooth muscle tonicity, endothelial barrier dysfunction, increased oxidative damage, impaired antithrombogenic properties, and perturbed angiogenic competence. Evidence suggests that dysregulation of TRPC4 and -C1 results in vascular endothelial barrier dysfunction; peer-00562775, version 1 -4 ACCEPTED MANUSCRIPT 2 malfunction of TRPP1 and -P2 impairs endothelial NO synthase; the reduced expression or activity of TRPC4 and -V1 impairs agonist-induced vascular relaxation; the decreased activity of TRPV4 reduces flow-induced vascular responses; and the activity of TRPC3 and -C4 is associated with oxidative stress-induced endothelial damage. In this review, we present a comprehensive summary of the literature on the role of TRP channels in endothelial cells, with an emphasis on endothelial dysfunction.
F1000 - Post-publication peer review of the biomedical literature, 2012
Major features of the transcellular signaling mechanism responsible for endothelium-dependent regulation of vascular smooth muscle tone are unresolved. We identified local calcium (Ca 2+) signals ("sparklets") in the vascular endothelium of resistance arteries that represent Ca 2+ influx through single TRPV4 cation channels. Gating of individual TRPV4 channels within a fourchannel cluster was cooperative, with activation of as few as three channels per cell causing maximal dilation through activation of endothelial cell intermediate (IK)-and small (SK)conductance, Ca 2+-sensitive potassium (K +) channels. Endothelial-dependent muscarinic receptor signaling also acted largely through TRPV4 sparklet-mediated stimulation of IK and SK channels to promote vasodilation. These results support the concept that Ca 2+ influx through single TRPV4 channels is leveraged by the amplifier effect of cooperative channel gating and the high Ca 2+ sensitivity of IK and SK channels to cause vasodilation. Endothelial cells (ECs) line all blood vessels and regulate the smooth muscle contractile state (tone). The concentration of intracellular free calcium ([Ca 2+ ] i) in ECs is increased by influx and by release from intra-cellular stores through inositol trisphosphate receptors (IP 3 Rs) in the membrane of the endoplasmic reticulum. Although Ca 2+-influx pathways are incompletely characterized, members of the transient receptor potential (TRP) family of nonselective cation channels have been implicated in this function. In particular, results from gene-knockout studies suggest that the vanilloid (TRPV) family member TRPV4 is involved in endothelium-dependent vascular dilation in response to flow and acetylcholine (ACh) (1-5).
Recent Developments in Vascular Endothelial Cell Transient Receptor Potential Channels
Circulation Research, 2005
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.)
TRPC channels in vascular cell function
Thrombosis and Haemostasis, 2009
The mammalian transient receptor potential (TRP) superfamily of nonselective cation channels can be divided into six major families. Among them, the "classical" or "canonical" TRPC family is most closely related to Drosophila TRP, the founding member of the superfamily. All seven channels of this family designated TRPC1-7 share the common property of receptor-operated activation through phospholipase C (PLC)coupled receptors, but their regulation by store-dependent mechanisms involving the proteins STIM and ORAi is still discussed contro-versially. This review will focus on the proposed functions of TRPC proteins in cells of the vascular system (e.g. platelets, smooth muscle cells and endothelial cells) and will present data concerning their physiological functions analysed in isolated tissues with down-regulated channel activity and in gene-deficient mouse models.
Heteromeric TRPV4-C1 channels contribute to store-operated Ca2+ entry in vascular endothelial cells
Cell Calcium, 2011
There is controversy as to whether TRP channels participate in mediating store-operated current (I SOC) and store-operated Ca 2+ entry (SOCE). Our recent study has demonstrated that TRPC1 forms heteromeric channels with TRPV4 in vascular endothelial cells and that Ca 2+ store depletion enhances the vesicle trafficking of heteromeric TRPV4-C1 channels, causing insertion of more channels into the plasma membrane in vascular endothelial cells. In the present study, we determined whether the enhanced TRPV4-C1 insertion to the plasma membrane could contribute to SOCE and I SOC. We found that thapsigargin-induced SOCE was much lower in aortic endothelial cells derived from trpv4 −/− or trpc1 −/− knockout mice when compared to that of wildtype mice. In human umbilical vein endothelial cells (HUVECs), thapsigargin-induced SOCE was markedly reduced by knocking down the expression of TRPC1 and/or TRPV4 with respective siRNAs. Brefeldin A, a blocker of vesicular translocation, inhibited the SOCE. These results suggest that an enhanced vesicular trafficking of heteromeric TRPV4-C1 channels contributes to SOCE in vascular endothelial cells. Vascular tension studies suggest that such an enhanced trafficking of TRPV4-C1 channels may play a role in thapsigargin-induced vascular relaxation in rat small mesenteric arteries.