Glucose enhances expression of TRPC1 and calcium entry in endothelial cells

N. B. Bishara, H. Ding


Hyperglycemia is a major risk factor for endothelial dysfunction and vascular disease, and in the current study, the link to glucose-induced abnormal intracellular Ca2+ (Cai2+) homeostasis was explored in bovine aortic endothelial cells in high glucose (HG; 25 mmol/l) versus low glucose (LG; 5.5 mmol/l; control). Transient receptor potential 1 (TRPC1) ion channel protein, but not TRPC3, TRPC4, or TRPC6 expression, was significantly increased in HG versus LG at 72 h. HG for 4, 24, and 72 h did not change basal Cai2+ or ATP-induced Cai2+ release; however, the amplitude of sustained Cai2+ was significantly increased at 24 and 72 h and reduced by low concentration of the putative, but nonspecific, TRPC blockers, gadolinium, SKF-96365, and 2-aminoethoxydiphenyl borate. Treatment with TRPC1 antisense significantly reduced TRPC1 protein expression and ATP-induced Ca2+ entry in bovine aortic endothelial cells. Although the link between HG-induced changes in TRPC1 expression, enhanced Ca2+ entry, and endothelial dysfunction require further study, the current data are suggestive that targeting these pathways may reduce the impact of HG on endothelial function.

  • bovine aorta endothelial cells
  • hyperglycemia
  • endothelial dysfunction
  • diabetes
  • transient receptor potential channels
  • store-operated calcium entry
  • transient receptor potential channel antisense

endothelial dysfunction, which can be defined from a functional view as the loss or reduction of endothelium-dependent vasodilatation to an endothelium-dependent vasodilator, such as acetylcholine, or to an increase in blood flow, is a very early indicator of the vascular disease that is closely associated with diabetes (3). Although there is a strong association between endothelial dysfunction and the development of cardiovascular disease, the cellular mechanism(s) remain poorly defined (13, 20, 40). The effects of hyperglycemia on endothelial nitric oxide (NO) synthase (eNOS) activity and NO generation are variable with suppressed basal NO levels reported for cultured endothelial cells with either no change or a decrease or an increase of eNOS expression and activity (11, 17, 18, 19, 49), whereas in streptozocin-induced diabetes in rats and mouse, an increase in eNOS expression has been described (16, 24).

A variety of stimuli that include circulating hormones, certain autacoids, shear stress, thrombin, and platelet-derived products activates endothelial cell eNOS as a result of an increase in intracellular Ca2+ (Cai2+) (55). Endothelial cells do not express voltage-dependent Ca2+ channels (53), and agonist-stimulated Ca2+ influx depends on the Ca2+ driving force and the opening of store-operated cation channels (SOCs) by a process referred to as capacitative Ca2+ entry or store-operated Ca2+ entry (SOCE) (31, 36, 41, 42). Although there is a lack of a clear understanding concerning how hyperglycemia affects eNOS function, Sheng et al. (49) reported that 5–7 days exposure of human vascular endothelial cells to 20 mmol/l glucose significantly impaired agonist-induced NO generation but was without effect on agonist-induced changes in Ca2+. In contrast, a 96-h exposure of human umbilical vein endothelial cells to 30 mM glucose induced apoptosis that was linked to an enhanced Ca2+ entry via SOCs (50).

Advances in our knowledge of SOCs indicate that stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum Ca2+ sensor and that the Ca2+ release-activated channel protein 1, Orai1, is the pore-forming subunit of the highly selective Ca2+ release-activated Ca2+ current (ICRAC) in endothelial cells (1). However, it has been previously argued that mammalian homologs of the transient receptor potential (TRP) gene family and notably the canonical TRPC subfamily of channels function as SOCs (43). Thus both TRPC1 and TRPC4 have been implicated in mediating SOCE in endothelial cells (23, 34). Indeed, TRPC1 has been shown to colocalize with Orai1 and STIM1, and studies with exogenously expressed TRPC1 and STIM1 in endothelial cells indicate that TRPC1 is regulated by STIM1 (26, 38). Furthermore, TRPC1 is ubiquitously expressed, primary endothelial cells in culture express TRPC1 to TRPC6 (23), and TRPC4 is an essential component, at least in the mouse, of NO-mediated endothelium-dependent relaxation (23, 37). Of particular interest to the question of the cellular basis of high glucose (HG)-induced endothelial dysfunction is the report from Kumar et al. (28) that an increase in vascular smooth muscle TRPC1 expression was associated with enhanced Ca2+ entry in human and animal vascular injury models and that the vascular injury associated with enhanced Ca2+ entry was reduced by an isoform-specific antibody against TRPC1. Finally, the TRPC1 gene, localized on human chromosome 3q22–24, a region closely associated with diabetic nephropathy, has been identified as a possible candidate gene in diabetic nephropathy (35).

Thus, to determine whether HG induced changes in TRPC function and SOCE in endothelial cells, the current study was designed to investigate 1) the effects of acute exposure to HG on ATP-stimulated Cai2+ release and SOCE in bovine aortic endothelial cells (BAECs); 2) the effects of HG on TRPC isoform expression; and 3) the use of TRPC1 antisense to investigate the link between HG, the expression of TRPCs, and Ca2+ entry.


Cell culture.

BAECs were isolated from bovine aortae obtained from a Melbourne-based abattoir as described previously (4). All experiments were conducted with BAECs cultured in Dulbecco's modified Eagle's medium with control 5.5 mmol/l glucose [low glucose (LG)] or 25 mmol/l glucose (HG) for 4, 24, or 72 h. An equimolar substitution of mannitol was used as an osmotic control.

Western blot analysis.

An equal amount of protein (30 μg) for each sample of cell lysates was separated by 8% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to a nitrocellulose membrane. Membranes were blocked by 5% skimmed milk for 1 h at room temperature and then incubated with the polyclonal human anti-TRPC1/3/4/6 (diluted 1:500) (anti-TRPC1/4 against cow were also purchased from Santa Cruz biotechnology for comparison, and similar results were obtained in preliminary studies to determine TRPC expression in BAECs) or anti-β-actin (diluted 1:2,000) antibodies overnight at 4°C. Membranes were washed three times in Tris-buffered saline with 0.05% Tween-20 and incubated for 1 h in secondary antibodies conjugated to horseradish peroxidase, and reaction products were visualized using enhanced chemiluminescence (Bio-Rad) and quantitated with Chemidoc software and normalized to the corresponding band density of β-actin.

Cai2+ measurement.

BAECs were loaded with 2 μmol/l fura-2 AM, changes in Cai2+ were determined as previously described, and data were presented as 340 nm-to-380 nm ratios obtained from groups of 10–12 single cells (5).

Antisense targeting.

Phosphorothionate-modified TRPC1 antisense 5′-T*T*C*T*CCTCCTTCACTT*C*C*C-3′ and sense 5′-A*A*G*A*GGAGGAAGTGAA*G*G*G*-3′ were synthesized and purified by Sigma. Cells were grown on glass coverslips and transfected with 2 μM TRPC1 antisense or sense using lipofectamine for 7 days according to the manufacturer's instructions with TRPC1 protein determined by Western blot analysis.

Chemicals and reagents.

Fura-2 AM (Molecular Probes, Eugene, OR), 2-aminoethoxydiphenyl borate (2-APB; Aldrich Chemical, Milwaukee, WI), and 1-{β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl}-1H-imidazole (econazole, SKF-96563) were prepared in dimethyl sulfoxide, gadolinium (Gd3+) chloride was prepared in distilled water, ATP (Sigma Chemical, St. Louis, MO) was dissolved in physiological salt solution, arachidonic acid (AA) (Sigma) was dissolved in 100% ethanol, all of which were aliquoted and kept frozen. Polyclonal human anti-TRPC1, -3, -4, and -6 and anti-β-actin antibodies were purchased from Alomone and Sigma.


Data are expressed as means ± SE with statistical comparisons performed using Excel software. Differences between two groups were evaluated with paired or unpaired Student's t-test as appropriate and differences between groups by one-way analysis of variance. Differences were considered to be significant when P < 0.05.


Ca2+ entry, but not Ca2+ release, is increased in BAECs treated with HG.

The two phases of Cai2+ changes were separated using a Ca2+ add-back protocol. Thus the P2Y receptor agonist ATP, when administered under Ca2+-free bath conditions, elicited an immediate, but transient, rise in Ca2+ with a sustained Ca2+ signal appearing upon the addition of extracellular Ca2+ (2 mmol/l). ATP-mediated Cai2+ signaling was studied in BAECs treated with HG for 4, 24, and 72 h. At 4 h (Fig. 1, A and D), no differences in the amplitude of the biphasic Cai2+ signals versus LG (248 ± 15 vs. 246 ± 13 for Cai2+ release and 257 ± 13 vs. 279 ± 18 for Ca2+ entry) were noted, but at 24 and 72 h (Fig. 1, B, E, and C, F), although the transient Cai2+ release levels (248 ± 19 vs. 246 ± 15 and 269 ± 19 vs. 267 ± 10, respectively) were not different, there was a significant increase (P < 0.05) in the sustained phase of Cai2+(240 ± 29 vs. 284 ± 17 at 24 h and 246 ± 9 vs. 297 ± 12 at 72 h respectively) in HG. Under comparable conditions, 25 mmol/l mannitol did not affect either basal or ATP-induced changes in Cai2+.

Fig. 1.

Intracellular Ca2+ (Cai2+) changes in bovine aortic endothelial cells (BAECs) treated with 5.5 mmol/l glucose [low glucose (LG); •] or 25 mmol/l glucose [high glucose (HG); ○] and stimulated with 1 μmol/l ATP in Ca2+-free solution. Arrows indicate time points for application of ATP. ATP induced initial Cai2+ release in Ca2+-free solution, and the subsequent application of Ca2+ induced a sustained increase in Cai2+ because of Cai2+ release-activated Ca2+ entry. BAECs in HG for 4 h (A), 24 h (B), and 72 h (C) are shown. A summary comparison of mean Cai2+ during the peak of Cai2+ release (t = 150 s) and plateau (t = 300 s) phase for the different time points are shown in D, E, and F. Data are means ± SE. *P < 0.05 compared with control.

TRPC1, TRPC3, TRPC4, and TRPC6 protein expression.

TRPC1, -3, -4, and -6 antibodies recognized the TRPC1, -3, -4, and -6 protein bands migrating at 115, 90, 100, and 120 kDa, respectively (Fig. 2A). Exposure to HG, but not 25 mmol/l mannitol, for 72 h resulted in a significant increase (P < 0.05%) in the expression of TRPC1 protein compared with LG, but with no significant differences in the expression of TRPC3, TRPC4, and TRPC6 (Fig. 2B).

Fig. 2.

A: representative gels for transient receptor potential channel (TRPC)1, TRPC3, TRPC4, and TRPC6 expression in BAECs in LG or HG for 72 h by Western blot analysis. B: summarization of densitometric analysis of detected TRPC proteins calculated as %β-actin. *P < 0.05 compared with control.

Antisense/TRPC1 treatment selectively attenuates TRPC1 expression in BAECs cultured in LG or HG.

The efficiency and specificity of the TRPC1 antisense was examined by Western blot analysis (Fig. 3, A and C). TRPC1 antisense markedly reduced TRPC1 protein expression in LG (13.4 ± 0.9) compared with nontreated (27.3 ± 2) or TRPC1 sense-treated BAECs (23.4 ± 1.7; P < 0.05%; Fig. 3, A and B). TRPC1 antisense also markedly reduced TRPC1 protein expression in HG for 72 h (antisense, 17.8 ± 0.8 vs. control, 39.5 ± 4.7; P < 0.05%; Fig. 3, A and B), but TRPC1 antisense treatment did not affect the expression of TRPC3, TRPC4, or TRPC6 proteins (P > 0.05%; Fig. 3, C and D).

Fig. 3.

TRPC1 protein expression in TRPC1 antisense-treated BAECs. A: representative gels for TRPC1 protein expression of BAECs untreated or treated with TRPC1 antisense or sense in LG, or treated with TRPC1 antisense in HG. C: representative gels of TRPCs protein expression with or without TRPC1 antisense treatment. Densitometric analysis of detected TRPC proteins calculated as %β-actin is summarized in B and D. *P < 0.05 compared with control.

Antisense/TRPC1 treatment attenuates ATP-induced Ca2+ responses.

Transient Ca2+ responses to ATP reflecting Ca2+ release from intracellular stores were not significantly different in nontreated or TRPC1 sense- or antisense-treated BAECs in LG versus HG (Fig. 4). Upon the addition of 2 mmol/l Ca2+, Ca2+ entry was significantly attenuated in TRPC1 antisense-treated cells in LG with mean data of 267 ± 21 and 253 ± 12, respectively, for untreated and sense-treated versus 190 ± 20 for antisense-treated cells (P < 0.001) and in HG with mean data of 360 ± 31 and 339 ± 16, respectively, for untreated and sense-treated versus 216 ± 21 for antisense-treated cells (P < 0.001) (Fig. 4).

Fig. 4.

Effect of antisense-mediated knockdown of TRPC1 protein on ATP-induced Cai2+ in BAECs. TRPC1 antisense- and sense-treated cells in LG (A) or HG (B) for 72 h are shown. Arrows indicate time points for application of ATP. Comparison of mean Cai2+ data during the peak release (t = 150 s) and plateau (t = 300 s) phase for the different conditions are shown (C). Data are means ± SE, presented as average of 5 tracings representing the response of 10–12 cells. *P < 0.001 compared with control.

TRPC1 antisense treatment does not affect AA-induced Ca2+ responses.

AA did not induce changes in Cai2+ when BAECs were maintained in a Ca2+-free solution; however, upon the subsequent application of Ca2+, AA evoked Ca2+ responses that were not significantly different in amplitude and time course in LG (235 ± 20) versus HG (239 ± 12) (P > 0.05%) (Fig. 5A). The Ca2+ entry response to AA after TRPC1 antisense was not significantly different from control (LG, 203 ± 10 vs. 235 ± 20; or HG, 214 ± 14 vs. 239 ± 12) (P > 0.05%) (Fig. 5B).

Fig. 5.

Effect of antisense-mediated knockdown of TRPC1 protein on arachidonic acid (AA) induced Cai2+ changes in BAECs. A: Cai2+ changes in the presence of 10 μmol/l AA between cells treated with LG or HG for 72 h. B: comparison of mean Cai2+ during the plateau (t = 360 s) phase following treatment of BAECs with 10 μmol/l AA either in LG or HG for 72 h. Data are means ± SE.

Effects of Gd3+, SKF-96365, and 2-APB reduce HG-mediated Ca2+ entry.

Although not specific for TRPCs or SOCE (24, 29, 37), SKF-96365 and Gd3+ are agents known to block Ca2+ entry and 2-APB is a putative TRPC1 blocker in sympathetic neurons (14). SKF-96365 decreased the sustained phase of Ca2+ entry in BAECs in LG (264 ± 27 vs. 219 ± 26; P < 0.05) and HG (287 ± 24 vs. 200 ± 26; P < 0.001) (Fig. 6, A–C). Gd3+ (1 μmol/l ) significantly decreased ATP-induced Ca2+ entry in LG (252 ± 7 vs. 178 ± 6; P < 0.001) and HG (306 ± 7 vs. 172 ± 6; P < 0.001) (Fig. 6, D–F). 2-APB at 75 μmol/l caused a significant inhibition of Ca2+ entry in LG (198.6 ± 13 vs. 287.8 ± 11; P < 0.001) or HG (199 ± 11 vs. 315 ± 14; P < 0.001) for 72 h (Fig. 6, G–I).

Fig. 6.

Effect of SKF-96365, Gd3+, and 2-aminoethoxydiphenyl borate (2-APB) on Cai2+ changes in BAECs. Cells were exposed to LG (A, D, and G) or HG (B, E, and H) for 72 h and incubated with 10 μmol/l SKF-96365 (A–C) or 1 μmol/l Gd3+ (D–F) or 75 μmol/l 2-APB (G–I). ATP (1 μmol/l) and/or Ca2+ (2 mmol/l) were added, indicated by the arrows. A direct comparison of mean Cai2+ during the peak of Cai2+ release (t = 160 s) and plateau (t = 310 s) phase for the different conditions are shown in C, F, and I. Data are means ± SE. *P < 0.001 compared with control.


An extensive literature supports the link between hyperglycemia and endothelial dysfunction (3, 47, 48, 52); however, the contribution of changes in Ca2+ homeostasis to endothelial dysfunction remains controversial (49, 50). In the present study, exposing BAECs to HG for 4, 24, or 72 h had no effect on the amplitude of Ca2+ released from the intracellular store but increased the sustained Ca2+ entry phase following the activation of the P2Y receptor after 24 and 72 h in HG. The enhancement of Ca2+ entry in HG was not related to an increase in the basal Ca2+ permeability of the cells, because there were no differences in the basal levels of cytosolic-free Ca2+ between BAECs in HG versus LG. Thus we conclude that HG enhances SOCE following P2Y activation. Furthermore, HG increased Ca2+ entry and the expression of TRPC1 protein in BAECs, and both parameters were normalized by treatment with TRPC1 antisense. In contrast, AA-mediated Ca2+ entry, which activates Ca2+ entry following metabolism to diacylglycerol via a process independent of store depletion and TRPC1 and has been reported to involve TRPC3, -6, and/or -7 (5, 10, 15), was unaffected by TRPC1 antisense treatment, thus supporting the view that the antisense treatment was selective for the TRPC1-mediated pathway. Hirano et al. (25) have, however, reported on the basis of small interfering RNA studies that protease-activated receptor 1-mediated SOCE requires STIM1 in porcine aortic endothelial cells. Furthermore, Abdullaev et al. (1) used small interfering RNA in human umbilical vein endothelial cells and demonstrated that the knockdown of STIM1 and Orai1, but not TRPC1 or TRPC4, significantly suppressed SOCE; in addition, either STIM1 or Orai1 silencing reduced ICRAC. In the absence of the measurement of ICRAC in the present study, it is not possible to conclude whether the SOCE-like event that was measured in BAECs is associated with the classic ICRAC now known to involve Orai1 or associated with a less-selective SOC (7). Additional studies of the effects of HG on endothelial cell SOCE are thus warranted, particularly because an enhanced expression of STIM1 and Orai1 has been reported in platelets from patients with type 2 diabetes and because an enhanced SOCE could explain the platelet hyperactivity and dysfunction seen in diabetes (58).

Our results are consistent with published data demonstrating that an exposure of human umbilical vein endothelial cells to 30 mmol/l glucose for 96 h was associated with an increase in the sustained Ca2+ SOC current (50) and in agreement with reports, for instance, in porcine aortic endothelial cells, that the short-term incubation of endothelial cells with HG amplifies agonist-induced changes in Cai2+ triggered by Ca2+-store depletion (57). However, HG inhibits agonist-induced changes in Cai2+ in mesangial and endothelial cells (33, 46), and Sheng et al. (49) reported an impairment in agonist-induced NO generation in endothelial cells to 20 mmol/l glucose for 5–7 days. Collectively, these results suggest that endothelial cells may react in a biphasic way to HG conditions with a short-term exposure resulting in an enhanced Cai2+ response to Ca2+ mobilizing agents and an increase in NO generation while chronic exposure to HG impairs function. Reports that NO generation and blood flow increased and peripheral resistance decreased in the early stages of diabetes (32, 51) whereas long-term diabetes leads to macro- and microangiopathy with reduced vascular reactivity (3, 52) lend support to the concept of HG-induced time-dependent changes in endothelial function. In addition, HG activates PKC, PKC-α activation also enhances Cai2+ via the activation of TRPC1 in human endothelial cells, and elevated PKC activity has been linked to the development of diabetes-related vascular disease (2, 12, 27). A potential link between an enhanced SOCE in endothelial cells and endothelial dysfunction is that, at least in neutrophils, SOCE is involved in the activation of NADPH oxidase; an increase in NADPH oxidase has been associated with endothelial dysfunction in streptozotocin-induced diabetic rats, and HG increased the expression of NADPH oxidase in an endothelial cell culture protocol (24, 29).

A highly selective small molecule inhibitor of SOCE or TRPC1 is not known, and thus we used 2-APB, Gd3+, and SKF-96365, which have been extensively used to probe the role of SOCE and TRPCs. All of these inhibitors have several off-target actions (38, 45, 46) including voltage-gated Ca2+ channels for SKF-96365 that, however, are not expressed in endothelial cells. 2-APB was originally described as an inositol 1,4,5-trisphosphate receptor inhibitor but also has other actions (22, 37, 45, 56). All three probes significantly decreased but did not completely inhibit the sustained phase of Cai2+ in response to ATP in BAECs in either LG or HG, a profile of action consistent with the contribution of a TRPC channel to ATP-induced Ca2+ entry in BAECs as well as the enhancement of Ca2+ entry following HG treatment (6, 30, 44). In a study of SOCE in hepatocytes, it was also demonstrated that Gd3+ incompletely inhibited Ca2+ entry, suggesting the contribution of other Ca2+ entry pathways (21). This conclusion is also supported by the data from the current study using TRPC1 antisense which also significantly reduced, but did not fully inhibit, Ca2+ entry. The activation of protease-activated receptor 1 in human umbilical vein endothelial cells results in TRPC1 mediating SOCE and TRPC6 in mediating receptor-operated Ca2+ entry (2); however, the relative contribution of SOCE versus receptor-operated Ca2+ entry may vary in an agonist-dependent manner (37). Thus it remains to be determined whether HG differentially affects SOCE and ICRAC or also affects other Ca2+ entry pathways. In this regard, Chung et al. (9) have reported a heightened contractility in saphenous veins from humans with an established diabetes for ∼11 years following a challenge with cyclopiazonic acid that is argued, based on a sensitivity to block by SKF-96365, to reflect an enhanced SOCE. mRNA, but not protein, for TRPC4 was enhanced, whereas mRNA for TRPC1 and TRPC6 was unchanged, but protein levels reduced (9). Collectively our data indicating that three nonspecific pharmacological blockers of TRPC as well as TRPC1 antisense significantly reduced HG-enhanced Ca2+ entry reinforce the hypothesis that an increase in TRPC1 expression is functionally linked to a hyperglycemia-mediated enhancement of Ca2+ entry in endothelial cells. Kumar et al. (28), with data based on their use of the Alomone TRPC1 antibody, reported an increase in both vascular smooth muscle TRPC1 expression and enhanced Ca2+ entry in human and animal vascular injury models and demonstrated that vascular injury was reduced by an isoform-specific antibody against TRPC1. Our data with BAECs extend this important observation, indicating that changes in TRPC1 expression may contribute to hyperglycemia-induced endothelial dysfunction. As already noted, the selectivity of TRPC1 antisense treatment is supported by the absence of an effect on ATP-evoked release of Ca2+ from intracellular stores in Ca2+-free medium in either LG or HG as well as the absence of an effect of TRPC1 antisense treatment on Cai2+ responses induced by AA.

The Western blot analysis data indicate that TRPC1, TRPC3, TRPC4, and TRPC6 mRNAs are expressed in BAECs. Other studies have shown the presence of two isoforms of TRPC1 (trpc1a and trpc1b), TRPC3, TRPC4, and TRPC5 in BAECs (30). We used a primary culture of BAECs with passages no greater than 5, and BAECs maintained in a HG for 72 h expressed a significantly higher level of TRPC1 protein that was associated with an augmented Ca2+ influx in response to a stored Ca2+ release by ATP. TRPC1 and TRPC4 have been shown to coimmunoprecipitate as a complex in BAECs (8). Although TRPC1 has been argued to be a key component of SOCs (39), data, as previously noted, from studies of human endothelial cells indicate that neither the knockdown of TRPC1 nor TRPC4 affected SOCE (1). Nonetheless, in our study, the antisense-mediated knockdown of TRPC1 protein and the resultant reduction of HG-induced enhanced Ca2+ entry with no change in protein levels for TRPC3, TRPC4, or TRPC6 suggest that it is unlikely, at least in BAECs, that TRPC1 forms functional heteromers with TRPC3, -4, or -6 and that TRPC1 does contribute to SOCE in BAECs. Further studies, however, are required to elucidate whether HG exposure also affects the expression of Orai1 or STIM1 and alters ICRAC.

Numerous effects of hyperglycemia on endothelial cell function have been described; however, the cellular processes whereby glucose alters Ca2+ homeostasis have remained unclear. As argued by Kumar et al. (28) and van Breemen et al. (54), an enhancement of Ca2+ entry can lead to cellular dysfunction and apoptosis. We present evidence that the exposure of endothelial cells to HG results in an enhanced expression of TRPC1 and an agonist-induced Ca2+ entry but not Cai2+ release. A selective antisense reduction of TRPC1 normalized Ca2+ homeostasis, thus strengthening previous arguments that TRPC1 is a potential therapeutic target for the treatment of vascular disease (28, 54).


This study was supported from a Research Infrastructure Grant from Royal Melbourne Institute of Technology University (to H. Ding) as well as Qatar Foundation National Priorities Research Program Grant 08-165-3-054.


No conflicts of interest are declared by the author(s).


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