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The canonical transient receptor potential channels (TRPCs) constitute a series of nonselective cation channels with variable degrees of Ca2+ selectivity. TRPCs consist of seven mammalian members, TRPC1, TRPC2, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7, which are further divided into four subtypes, TRPC1, TRPC2, TRPC4/5, and TRPC3/6/7. These channels take charge of various essential cell functions such as contraction, relaxation, proliferation, and dysfunction. This review, organized into seven main sections, will provide an overview of current knowledge about the underlying pathogenesis of TRPCs in cardio/cerebrovascular diseases, including hypertension, pulmonary arterial hypertension, cardiac hypertrophy, atherosclerosis, arrhythmia, and cerebrovascular ischemia reperfusion injury. Collectively, TRPCs could become a group of drug targets with important physiological functions for the therapy of human cardio/cerebro-vascular diseases.
In 1969, Cosens and Manning (1969) discovered that Drosophila with mutations in a peculiar gene was defective and displayed transient light-induced receptor potentials (TRPs) in response to continuous light exposure, causing visual impairment in photoreceptor cells. This phenomenon was explained by a deletion in ion channels, and led to the discovery of “TRP genes” that were named TRP channels. To date, the TRP channels superfamily contains 28 members in mammals and is subdivided into six subfamilies: TRPA, TRPC, TRPML, TRPM, TRPN, TRPV and TRPP, all of which permeate cations (Montell, 2005). The canonical transient receptor potential channels (TRPCs) are the first encoded TRP gene family in mammals and are the most dominating non-voltage-gated, Ca2+-permeable cation channels in various cells (Zhu et al., 1995). TRPCs fall into four groups in terms of their amino acid homology and similarities in function: TRPC1, TRPC2 (as a pseudogene in humans), TRPC4/5, and TRPC3/6/7 (Table 1) (Nilius and Voets, 2005; Minke, 2006). The seven subtypes have an invariant sequence in common in the C-terminal tail called a TRP box (Philipp et al., 2000) and include three to four ankyrin-like repetitive sequences in the N-terminus (Montell et al., 2002). Many subunits of TRPCs are able to coassemble. There exist heteromultimeric channels that consist of heterologously expressed and endogenous TRPC monomers (Nilius et al., 2007). Indeed, TRPC1, TPRC4 and TRPC5 can form heteromers. Similarly, TRPC3, TRPC6, and TRPC7 form heteromers. In terms of activation mechanisms, members of the TRPC3, TRPC6 and TRPC7 subtypes can be stimulated by diacylglycerol (DAG) (Hofmann et al., 1999), which is the phospholipase C (PLC)-derived production regulating their physiological activation. In contrast, the TRPC1/4/5 subgroups are completely insensitive to DAG, which is still a controversial mechanism (Venkatachalam et al., 2003).
Most TRPCs are inserted in the plasma membrane (PM) and can be hindered by blockers (Zhang et al., 2013). Generally speaking, G protein-coupled receptors (GPCRs) have important roles in the regulation of TRPCs. In some cases, lipid signals can regulate the signals from GPCRs to TRPCs (Kukkonen, 2011).
A cytosolic Ca2+ change may be induced by activation of specific GPCRs, including an initial transient increase resulting from release of calcium ions from the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) and a subsequent sustained plateau phase via receptor-operated channels (ROCs) (Berridge et al., 2003). This latter manner of Ca2+ entry is named “receptor-operated Ca2+ entry” (ROCE) (Soboloff et al., 2005; Inoue et al., 2009). Another manner of Ca2+ entry has been termed “store-operated Ca2+ entry” (SOCE) via store-operated channels (SOCs) (Shi et al., 2016). SOCE occurs linked to depletion of intracellular Ca2+ stores (Putney, 1986; Ng and Gurney, 2001). Ca2+ refills depleted intracellular Ca2+ storages, directly accessing the SR/ER via SOCE. Although the exact functional relationship between TRPC and SOCE/ROCE is still indistinct, it is clear that TRPCs are the main channels of SOCs and ROCs. In recent years, SOCs and ROCs have gained increased attention for their role in mediating Ca2+ influx in response to cell function and disease. Previous studies suggested that TRPC family members, except TRPC2, are detectable at the mRNA level in the whole heart, vascular system, cerebral arteries, smooth muscle cells (SMCs) and endothelial cells (ECs) (Yue et al., 2015). TRPCs may participate in most cardio/cerebro-vascular diseases (Table 2) and play important roles in reactive Ca2+-signaling in the cardio/cerebro-vascular system (Fig. 1).
Hypertension is a chronic cardiovascular disease characterized by persistently elevated blood pressure and is a major risk factor for coronary artery disease, stroke, heart failure, and peripheral vascular disease. In recent years, numerous studies have focused on the relationship between primary hypertension and TRPCs (Fuchs et al., 2010). In pathological states, some signaling factors are involved in the transition of SMCs into the proliferative phenotype, leading to an excessive growth of SMCs (Beamish et al., 2010). Abnormal over-growth of SMCs is implicated in various vascular diseases, including hypertension (Beamish et al., 2010). Previous studies have convincingly suggested that several TRPC members are involved in hyperplasia of SMCs. TRPC1/3/6 all have been involved in enhanced proliferation and phenotype switching of SMCs (Dietrich et al., 2005; Takahashi et al., 2007; Koenig et al., 2013). Kumar et al. (2006) suggested that TRPC1 was up-regulated in rodent vascular injury models and in human neointimal hyperplasia after vascular damage. In coronary artery SMCs, upregulation of TRPC1 results in angiotensin-II (Ang II)-mediated human coronary artery SMC proliferation (Takahashi et al., 2007). Moreover, other studies found that the visible whole-cell currents were triggered by passive depletion of Ca2+ storages in vascular smooth muscle cells (VSMCs) in wild type mice, but not in Trpc1−/− mice (Shi et al., 2012), suggesting TRPC1 contributed to the alteration of whole-cell currents in VSMCs (Shi et al., 2012).
In addition, TRPC3 also plays a pivotal role in Ca2+ signaling and a pathophysiological role in hypertension. The previous studies suggested TRPC3 levels were elevated in patients with hypertension as well as in the pressure-overload rat and the spontaneous hypertensive rat (SHR) models (Liu et al., 2009; Onohara et al., 2006; Thilo et al., 2009). In monocytes, DAG-, thapsigargin-and Ang II-induced Ca2+ influxes were elevated in response to pathological state in SHR. However, further studies proved that downregulating TRPC3 by siRNA or applying with Pyrazole-3 (Pyr3), a highly selective inhibitor of TRPC3, reduced DAG-, thapsigargin- and Ang II-induced Ca2+ influx in monocytes from SHR (Liu et al., 2007a; Chen et al., 2010), prevented stent-induced arterial remodeling, and inhibited SMC proliferation (Yu et al., 2004; Schleifer et al., 2012). Similarly, compared with normotensive patients, increased expression of TRPC3 and a subsequent increase in SOCE has been noticed in monocytes from hypertension patients (Liu et al., 2006, 2007b). These data show a positive association between blood pressure and TRPC3, indicating an underlying role for TRPC3 in hypertension.
TRPC6 is a ubiquitous TRPC isoform expressed in the whole vasculature, which plays a pivotal role in blood pressure regulation because of its physiological importance in both receptor-mediated and pressure-induced increases of cytosolic Ca2+ in VSMCs (Toth et al., 2013). Studies suggested that cGMP-dependent protein kinase I (cGKI), which was implicated in the regulation of smooth muscle relaxation, inhibited the activity of TRPCs in SMCs (Kwan et al., 2004; Takahashi et al., 2008; Chen et al., 2009; Dietrich et al., 2010) and regulated vascular tone via endothelial nitric oxide (NO) (Loga et al., 2013). However, the knockout of TRPC6 might injure endothelial cGKI signaling and vasodilator tone in the aorta (Loga et al., 2013). Although deletion of TRPC6 decreases SMC contraction and depolarization induced by pressure in arteries, the basal mean arterial pressure in Trpc6−/− mice is about more than 7 mm Hg higher than that in wild type mice (Welsh et al., 2002; Dietrich et al., 2005), indicating that TRPC6 participated in smooth muscle contraction. Similarly, in deoxycorticosterone acetate (DOCA)-salt-hypertensive rats, overexpression of TRPC6 strengthened agonist mediated VSMC contractility companied with increased mean blood pressure (Bae et al., 2007). Additionally, mineralocorticoid receptor-induced TRPC6 mRNA level was elevated in the aldosterone-treated rat A7r5 VSMCs, suggesting that heightened TRPC6 expression importantly participates in increased VSM reactivity (Bae et al., 2007).
Pulmonary arterial hypertension (PAH) is characterized by a thickening of the pulmonary arterial walls, which can cause right heart failure (Yu et al., 2004). Increased pulmonary vascular resistance is a primary factor in the progression of PAH. Ca2+ entry from the extracellular space, acting as a crucial mediator, is implicated in vasoconstriction (through its pivotal effect on pulmonary artery smooth muscle cells (PASMCs) contraction) and vascular remodeling (through its stimulatory effect on PASMC proliferation) (Kuhr et al., 2012; Weber et al., 2015). The most frequently expressed isoforms of TRPC in VSMCs are TRPC1, TRPC4, and TRPC6; TRPC3, TRPC5, and TRPC7 are less frequently detected (Inoue et al., 2006; Maier et al., 2015). Studies showed that Ca2+ entry improved the level of cytosolic Ca2+ through SOCs and ROCs (which is formed by TPRCs), and sufficient Ca2+ in the SR induced VSMC proliferation (Birnbaumer et al., 1996; Golovina et al., 2001; Bergdahl et al., 2003; Satoh et al., 2007; Seo et al., 2014).
TRPC1, TRPC4 and TRPC6 are involved in hypoxic pulmonary vasoconstriction, which is related to increased SOCE. Additionally, SOCE contributes to basal intracellular Ca2+ concentration ([Ca2+]i) and the proliferation and migration of PASMCs in rat (Lu et al., 2008). Malczyk et al. (2013) demonstrated that TRPC1 played an important role in hypoxia-induced PAH, as hypoxia-induced PAH is alleviated in Trpc1−/− mice. Xia et al. (2014) found that TRPC1/6 are crucial for the regulation of neo-muscularization, vasoreactivity, and vasomotor tone of pulmonary vasculatures; the combined actions of the two channels have a distinctly larger influence using Trpc1−/−, Trpc6−/− and Trpc1−/−/Trpc6−/− mice. Significantly, another study confirmed the upregulation of TRPC1/6 expression in murine chronic hypoxia PAH models (Wang et al., 2006). Silence of TRPC1 and TRPC6 specifically attenuated thapsigargin-and 1-oleoyl-2-acetyl-sn-glycerol (OAG)-induced cation entries, respectively, indicating that TRPC1-mediated SOCE and TRPC6-mediated ROCE are upregulated by chronic hypoxia (Lin et al., 2004). TRPC4 is also involved in PAH. In monocrotaline-induced PAH rats, TRPC1 and TRPC4 protein levels were both increased significantly, resulting in enhanced vasoconstriction to endothelin-1 (ET-1) (Liu et al., 2012). In addition, siRNA specifically targeting TRPC4 reduced increases in TRPC4 expression and capacitative calcium entry (CCE) amplitude and inhibited ATP-induced PASMC proliferation (Zhang et al., 2004).
The expression and function of TRPCs are variously regulated by molecules in PAH. Wang et al. (2015) implied that both bone morphogenetic protein-4 (BMP4) and hypoxia inducible factor-1α (HIF-1α) upregulated TRPC1 and TRPC6, leading to elevated basal [Ca2+]i in PASMCs, driving the development of chronic hypoxia-induced PAH (Wang et al., 2015). Another study found that TRPC expression was found absent in mice partially deficient for HIF-1α (Wang et al., 2006). In human PASMCs, siRNA of the HIF-1α reduced hypoxia-induced BMP4 expression and knockout of either HIF-1α or BMP4 abrogated hypoxia-induced basal cytosolic Ca2+ increase and TRPC expression (Zhang et al., 2014; Wang et al., 2015). Also, TRPCs have been recognized as reactive oxygen species (ROS)-activated channels and it is suggested that they are critical for hypoxia associated with vascular regulatory procedures in lung tissue.
TRPCs could be regulated by pharmacological intervention during PAH. The treatment of experimental PAH with sildenafil and sodium tanshinone IIA sulfonate suppresses TRPC1/6 expression (Lu et al., 2010; Wang et al., 2013a). SAR7334, an inhibitor of TRPC6, suppresses native TRPC6 activity in vivo (Maier et al., 2015) and opens new opportunities for the investigation of TRPC function. In the lung and PASMC from idiopathic PAH patients, the mRNA and protein expression levels of TRPC6 were much higher than that from normotensive or secondary PAH patients. Also, inhibition of TRPC6 expression markedly attenuated idiopathic PAH-PASMC proliferation (Yu et al., 2004). As a consequence, the participation of TRPC1/4/6 are crucial for PAH.
These results suggest that overexpression of TRPC may partially contribute to the increased PASMC proliferation, hinting at a promising therapeutic strategy for PAH patients.
Cardiac hypertrophy serves as a common pathway in cardiovascular diseases. It is the most important pathological foundation resulting in cardiogenic death. Although one study showed that the knockout of some TRPC genes did not result in abnormality in normal mice hearts (Yue et al., 2015). TRPCs have been demonstrated to play an important role in the pathological progress of cardiac hypertrophy through the mediation of ion channel activities and downstream signaling. Dysregulation of TRPCs may lead to maladaptive cardiac hypertrophy.
Numerous studies have shown that TRPC expression and activity are up-regulated in pathological cardiac hypertrophy (Bush et al., 2006; Kuwahara et al., 2006; Ohba et al., 2007; Seth et al., 2009). Cardiac hypertrophy induced by transverse aortic constriction (TAC) was improved in Trpc1−/− mice. Meanwhile, downregulation of TRPC1 reduced SOCE and prevented ET-1-, Ang II-, and phenylephrine (PE)-induced cardiac hypertrophy, indicating that deletion of TRPC1 avoided harmful influences in response to increased cardiac stresses in Trpc1−/− mice (Ohba et al., 2007). Also verified that TRPC1-mediated Ca2+ entry stimulated hypertrophic signaling in cardiomyocytes (Seth et al., 2009). Similarly, cardiac pathological hypertrophy could be caused by stimulation of pressure overload or overexpression of the TRPC3 gene in cardiomyocytes from TRPC3 transgenic mice, and could be selectively inhibited by Pyr3 (Nakayama et al., 2006; Kiyonaka et al., 2009). Also, TRPC6 has been proposed as a critical target of anti-hypertrophic effects elicited via the cardiac ANP/BNP-GC-A pathway (Kinoshita et al., 2010). However, a recent study showed Trpc6−/− mice resulted in an obvious augment in the cardiac mass/tibia length (CM/TL) ratio after Ang II, while the Trpc3−/− mice showed no alteration after Ang II injection. However, the protective effect against hypertrophy of pressure overload was detected in Trpc3−/−/Trpc6−/− mice rather than in Trpc3−/− or Trpc6−/− mice alone (Seo et al., 2014). Similarly, the newly developed selective TRPC3/6 dual blocker showed an obvious inhibition to myocyte hypertrophy signaling activated by Ang II, ET-1 and PE in a dose-dependent manner in HEK293T cells as well as in neonatal and adult cardiomyocytes (Seo et al., 2014).
Although the TRPCs role in myocardial hypertrophy is controversial, it is generally believed that calcineurin-nuclear factor of activated T-cells (Cn/NFAT) is a critical factor of microdomain signaling in the heart to control pathological hypertrophy. Studies found that transgenic mice that express dominantnegative myocyte-specific TRPC3, TRPC6 or TRPC4 attenuated the reactivity following either neuroendocrine-like or pressure overload-induced pathologic cardiac hypertrophy through Cn/NFAT stimulation in vivo, demonstrating that blockades of TRPCs are necessary adjusters of hypertrophy (Dietrich et al., 2006; Wu et al., 2010; Eder and Molkentin, 2011).
Undoubtedly, TRPCs play an important role in cardiac hypertrophy and can be regarded as new therapeutic target in the development of new drugs.
Atherosclerosis is commonly considered a chronic disease with dominant accumulation of lipids and inflammatory cells of the arterial wall throughout all stages of the disease (Tabas et al., 2010). Several types of cells such as VSMCs, ECs, monocytes/macrophages, and platelets are involved in the pathological mechanisms of atherosclerosis.
It has been reported that the participation of proliferative phenotype of VSMCs is a consequential part in atherosclerosis. Cytoplasmic Ca2+ dysregulation via TRPC1 can mediate VSMC proliferation (Edwards et al., 2010). Studies have established that TRPC1 is implicated in coronary artery disease (CAD), during which the expression of TRPC1 mRNA and protein are elevated (Cheng et al., 2008; Edwards et al., 2010). Kumar et al. (2006) showed the upregulated TRPC1 in hyperplastic VSMCs was related to cell cycle activity and enhanced Ca2+ entry using a model of vascular injury in pigs and rats. In addition, the inhibition of TRPC1 effectively attenuates neointimal growth in veins (Kumar et al., 2006). These results indicate that upregulation of TRPC1 in VSMCs is a general feature of atherosclerosis.
The vascular endothelium is a polyfunctional organ, and ECs can generate extensive factors to mediate cellular adhesion, smooth muscle cell proliferation, thromboresistance, and vessel wall inflammation. Vascular endothelial dysfunction is the earliest detectable manifestation of atherosclerosis, which is associated with the malfunction of multiple TRPCs (Poteser et al., 2006). Tauseef et al. (2016) showed that TRPC1 maintained adherens junction plasticity and enabled EC-barrier destabilization by suppressing sphingosine kinase 1 (SPHK1) expression to induce endothelial hyperpermeability. Also, Poteser et al. (2006) demonstrated that porcine aorta endothelial cells, which co-expressed a redox-sensitive TRPC3 and TRPC4 complex, could give rise to cation channel activity. Furthermore, mice transfected with TRPC3 showed increased size and cellularity of advanced atherosclerotic lesions (Smedlund et al., 2015). In addition, studies further supported the relevance of EC migration to the healing of arterial injuries, suggesting TRPC5 and TRPC6 were activated by hypercholesterolemia, which impairs endothelial healing in vitro and in vivo (Rosenbaum et al., 2015; Chaudhuri et al., 2016).
Monocyte activation, adhesion to the endothelium, and transmigration into the sub-endothelial space are critical for early pathogenesis of atherosclerosis. The roles of TRPCs have been identified in the macrophage efferocytosis and survival, two crucial events in atherosclerosis lesion development (Tano et al., 2012). It has been shown that high D-glucose or peroxynitrite-induced oxidative stress significantly increased the expression of TRPCsin human monocytes (Wuensch et al., 2010). Vascular cell adhesion molecule-1 (VCAM-1) is important in monocyte recruitment to the endothelium as a critical factor in the development of atherosclerotic lesions. Smedlund et al. suggested that inhibition of TRPC3 expression could significantly attenuate ATP-induced VCAM-1 and monocyte adhesion (Smedlund and Vazquez, 2008; Smedlund et al., 2010), indicating TRPC3 is involved in atherosclerosis lesion development. The platelet also plays important roles in cardiovascular diseases, especially in atherosclerosis, by participating in the formation of thrombosis and the induction of inflammation (Wang et al., 2016). Liu et al. (2008) investigated platelets in type II diabetes mellitus (DM) patients and found a time-dependent and concentration-dependent amplification of TRPC6 expression on the platelet membrane after challenge with high glucose. These results indicate that the incremental expression and activation of TRPC6 in platelets of DM patients may result in the risk of increasing atherosclerosis.
In summary, the pathophysiological relevance of TRPCs in several critical progresses has been linked to atherosclerosis.
Arrhythmia is a group of conditions in which the electrical activity of the heart is irregular, either too fast (above 100 beats per minute, called tachycardia) or too slow (below 60 beats per minute, called bradycardia). Several experiments have shed light on TRPC-regulated Ca2+ entry in arrhythmia. Sabourin et al. (2011) found that the existence of TRPC1,3,4,5,6 and 7 in the atria and ventricle, via association with the L-type voltagegated calcium channel (LTCC), plays a role in the modulation of cardiac pacemaking, conduction, ventricular activity, and contractility during cardiogenesis. Mechanical stretch is one of the causes of cardiac arrhythmia. It has been demonstrated that mechanical transformation of ventricular myocytes can modulate TRPC6. The process can be inhibited by GsMTx-4, which is a peptide isolated from tarantula venom and a specific inhibitor of stretch-activated channels (SAC) (Dyachenko et al., 2009; Anderson et al., 2013; Gopal et al., 2015).
One of the most common arrhythmias is atrial fibrillation (AF) (Nattel, 2011; Wakili et al., 2011). By researching fibroblast regulation by Ca2+-permeable TRPC3, Harada et al. (2012) found that AF increased expression of TRPC3 by activating NFAT-mediated downregulation of microRNA-26. Further, they found that AF induced TRPC3-dependent increase of fibroblast proliferation and differentiation, likely by mediating the Ca2+ entry that stimulates extracellular signal-regulated kinase signaling. TRPC3 blockade prevented AF substrate development in a dog model of electrically maintained AF in vivo (Harada et al., 2012). In conclusion, by promoting fibroblast pathophysiology, TRPC3 is likely to play an important role in AF.
Tissue injury led by ischemia reperfusion is the main cause of cell apoptosis and necrosis leading to myocardial infarction, stroke, and other deadly diseases. After focal cerebral ischemia, brain injury results from a suite of pathological progresses, including inflammation, excitotoxicity, and apoptosis. Researchers have indicated that an increase in cytosolic Ca2+ is a critical step in initiating myocardial cell apoptosis and necrosis responding to ischemia reperfusion (Carafoli, 2002; Brookes et al., 2004). Several Ca2+ entry pathways, including the CCE and the Na+/Ca2+ exchanger channel, have been implicated in mediating myocardial cell Ca2+ overload (Carafoli, 2002; Brookes et al., 2004; Piper et al., 2004). An increasing number of studies show that members of the TRPC proteins are involved in regulating CCE. Given this growing evidence linking TRPC proteins to CCE in myocardial cells subjected to ischemia reperfusion injury, Liu et al. (2016) tested the assumption that increased expression of TRPC3 in myocardial cells results in increased sensitivity to the injury after ischemia reperfusion, and found that the treatment of CCE inhibitor SKF96365 markedly improved cardiomyocytes viability in response to overexpressed TRPC3. In contrast, the LTCC inhibitor verapamil had no effect (Shan et al., 2008; Liu et al., 2016). These data strongly indicate that CCE mediated through TRPCs may lead to Ca2+-induced cardiomyocyte apoptosis caused by ischemia reperfusion injury.
Intracellular Ca2+ overload is also the major reason of neuronal death after cerebral ischemia. TRPC6 protein is hydrolyzed by the activation of calpain induced by intracellular Ca2+ overload in the neurons after ischemia, which precedes ischemic neuronal cell death. The inhibition of proteolytic degeneration of TRPC6 protein by blocking calpain prevented ischemic neuronal death in an animal model of stroke (Du et al., 2010). Studies found that the upregulated TRPC6 could activate downstream effectors cAMP/Ca2+-response elementbinding (CREB) proteins, which are activated in neurons linked to a number of stimuli including growth factors, hormones, and neuronal activity through the Ras/MEK/ERK and CaM/CaMKIV pathways (Shaywitz and Greenberg, 1999; Tai et al., 2008; Du et al., 2010). It was also demonstrated that enhanced CREB activation activated neurogenesis, avoided myocardial infarct expansion, and reduced the penumbra region of cerebral ischemia and infarct volumes (Zhu et al., 2004). Thus, TRPC6 neuroprotection relied on CREB activation. Similarly, Lin et al. (2013) demonstrated that resveratrol prevented cerebral ischemia/reperfusion injury through the TRPC6-MEK-CREB and TRPC6-CaMKIV-CREB pathway.
The aforementioned results provide further evidence that TRPC3 and TRPC6 play roles in the mediation of cardiomyocyte function and suggest that TRPC3 and TRPC6 may contribute to increased tolerance to ischemia reperfusion injury.
Mechanisms including elevated activation or expression of TRPCs that partake in mediating Ca2+ influx activated by GPCRs offer the chance to interfere with Ca2+-dependent signaling processes, thus playing a significant role in cardio/cerebro-vascular diseases. The primary regulatory paradigm for most of these activities takes charge of total cytosolic Ca2+ or the propagation of intracellular Ca2+ signaling events that regulate cellular activity. Strong evidence indicates that TRPCs conduce to mechanical and agonist-induced SMC or fibroblast proliferation, cardiomyocytes apoptosis, and endothelium dysfunction. TRPCs were also present in Ang II-induced endothelium-dependent vasodilation and elevated contractility, regulation of vascular angiogenesis to participate in hypertension, pulmonary arterial hypertension, cardiac hypertrophy, atherosclerosis, arrhythmia, and ischemia reperfusion injury. These new findings permit a more comprehensive assessment of the molecular and cellular importance of TRPCs in physiology and pathophysiology.
Many questions remain to be elucidated. Therefore, researchers should keep a watchful eye on how the novel effects of TRPCs can be committed to human cardio/cerebro-vascular diseases and clarify the clinical relevance of TRPC activities. An improved understanding of the underlying mechanisms of cardiovascular and cerebrovascular diseases may assist in the design of new therapies and the identification of more selective pharmacological agonists and antagonists (Table 3) for TRPCs or interdependent channels as well as promote exciting chances to develop new therapies that prevent or treat cardio/cerebro-vascular diseases.
This work was supported by the grants from the National Natural Science Foundation of China (No. 81370241 and 81170107 to X. Q. Li) and the Social Development and Scientific and Technological Research Projects of Shaanxi province (No. 2015SF193 to X. Q. Li).