TRP channel and cardiovascular disease

Pharmacology & Therapeutics 118 (2008) 337–351

Contents lists available at ScienceDirect

Pharmacology & Therapeutics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p h a r m t h e r a

Associate editor: M. Endoh

TRP channel and cardiovascular disease Hiroyuki Watanabe a, Manabu Murakami b, Takayoshi Ohba a, Yoichiro Takahashi a, Hiroshi Ito a,⁎ a b

Second Department of Internal Medicine, Akita University School of Medicine 1-1-1, Hondoh, Akita 010-8543, Japan Department of Pharmacology, Akita University School of Medicine, Akita, Japan

A R T I C L E

I N F O

Keywords: TRP channel superfamily Calcium Cardiac hypertrophy Vasoconstriction Vascular remodeling Endothelial dysfunction Abbreviations: ADPKD, autosomal dominant polycystic kidney disease Ang II, angiotensin II [Ca2+]i, intracellular Ca2+ concentration CB, cannabinoid CGRP, calcitonin gene-related peptide cAMP, cyclic adenosine monophosphate DA, ductus arteriosus DAG, diacylglycerol DASMC, ductus arteriosus smooth muscle cell DMD, Duchenne muscular dystrophy EDHF, endothelium-derived hyperpolarizing factor EETs, epoxyeicosatrienoic acids ER, endoplasmic reticulum ET, endothelin GATA, GATA-binding protein hCASMC, human coronary artery smooth muscle cell HIF-1, hypoxia-inducible factor 1 HUVEC, human umbilical vein endothelial cell IP3, inositol-1,4,5-triphosphate IPAH, idiopathic pulmonary arterial hypertension LGC, ligand gated channel [Mg2+]i, intracellular Mg2+ concentration NCX, Na+/Ca2+ exchanger NFAT, nuclear factor of activated T cells NO nitric oxide NSCC, nonselective cation channel PAEC, pulmonary artery endothelial cell PASMC, pulmonary artery smooth muscle cell PDGF, platelet-derived growth factor PE, phenylephrine PKA, protein kinase A PKC, protein kinase C PL, phospholipase RAC, receptor-activated cation channel RNS, reactive nitrogen species

A B S T R A C T The transient receptor potential (TRP) channel superfamily consists of 28 mammalian cation channels and is expressed in almost every tissue, including the heart and vasculature; most TRP channels are permeable to Ca2+ and are prime molecular candidates for store-operated channels (SOCs), receptor-operated channels (ROCs), ligand-gated channels (LGCs) and stretch-activated channels (SACs). As these channels act as multifunctional cellular sensors and are involved in several fundamental cell functions such as contraction, proliferation and cell death, investigation of their roles in human disease is very important. This review presents an overview of current knowledge about the pathological role of TRP channels in cardiovascular diseases and highlights some TRP channels for which a role in the diseases can be anticipated. Evidences suggest that up-regulation of TRPC channels is involved in the development of cardiac hypertrophy and heart failure; TRPM4 participates in some features of cardiac arrhythmias; increased expression of TRPC channels is associated with vascular remodeling and pulmonary hypertension; reduced expression or activity of TRPV4 impairs endothelium-dependent vasorelaxation; TRPC3/C4 and TRPM2 act as endothelial redox sensors; and TRPC1, -C4, -C6, -V4, and -M2, have been implicated in endothelial barrier dysfunction. Ultimately, TRP channels will become important novel pharmacological targets for the treatment of human cardiovascular diseases. © 2008 Elsevier Inc. All rights reserved.

⁎ Corresponding author. Tel.: +81 18 884 6110; fax: +81 18 836 2182. E-mail address: [email protected] (H. Ito) 0163-7258/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2008.03.008

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ROC, receptor-operated channel ROS, reactive oxygen species S1P, sphingosine-1-phospate SAC, stretch-activated channel SAH, subarachnoid hemorrhage SERCA, sarcoplasmic/endplasmic reticulum Ca2+ ATPase SHR, spontaneously hypertensive rats SMC, smooth muscle cell SOC, store-operated channels SOCE, store-operated Ca2+ entry SR, sarcoplasmic reticulum STIM1, stromal interaction molecule 1 TM, transmembrane spanning helices TRP, transient receptor potential TRPA, transient receptor potential cation channel subfamily A TRPC, transient receptor potential cation channel subfamily C TRPM, transient receptor potential cation channel subfamily M TRPML, transient receptor potential cation channel subfamily ML TRPP, transient receptor potential cation channel subfamily P TRPV, transient receptor potential cation channel subfamily V UTP, uridine 5'-triphosphate VEGF, vascular endothelial growth factor VGCC, voltage-gated Ca2+ channel VSMC, vascular smooth muscle cell WKY, Wistar-Kyoto rats

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The TRP superfamily . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TRP channels in the heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Regulatory role of TRPC channels in the development of cardiac hypertrophy . . . 3.2. TRPC channels and failing myocardium . . . . . . . . . . . . . . . . . . . . . 3.3. Pathological role of TRP channels in the heart in muscular dystrophy . . . . . . 3.4. Involvement of TRP channels in pacemaking in the sinoatrial node. . . . . . . . 3.5. TRPM4 channel participates in the triggering of arrhythmias. . . . . . . . . . . 3.6. TRPP2 channels and cardiac defects . . . . . . . . . . . . . . . . . . . . . . 3.7. TRPV1 channel in cardiac sensory neurons . . . . . . . . . . . . . . . . . . . 3.8. TRPC channels in cardiac fibroblasts . . . . . . . . . . . . . . . . . . . . . . 4. TRP channels in the vasculature . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. TRP channels and the growth of vascular smooth muscle cells . . . . . . . . . . 4.1.1. Functional role of TRP channels in vascular remodeling . . . . . . . . . 4.1.2. TRP channels and idiopathic pulmonary hypertension . . . . . . . . . . 4.2. TRP channels and vasoconstriction . . . . . . . . . . . . . . . . . . . . . . . 4.2.1. TRP channels and agonist-induced vasoconstriction . . . . . . . . . . . 4.2.2. Involvement of TRPC channels in cerebral vasospasm after aneurysmal subarachnoid hemorrhage . . . . . . . . . . . . . . . . . 4.2.3. TRP channels control arterial myogenic tone . . . . . . . . . . . . . . 4.2.4. TRP channels and hypoxic pulmonary vasoconstriction . . . . . . . . . 4.2.5. TRP channels and normoxic contraction of the ductus arteriosus . . . . 4.3. Vascular complications in autosomal-dominant polycystic kidney disease (ADPKD) 4.4. TRPV1 channel in perivascular sensory nerves . . . . . . . . . . . . . . . . . 4.5. TRP channels and endothelium-dependent vasodilatation . . . . . . . . . . . . 4.6. TRP channels as an endothelial redox sensor . . . . . . . . . . . . . . . . . . 4.7. TRPC channels regulate endothelial barrier function . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Calcium ions (Ca2+) play an important role in many cellular responses. For example, Ca2+ controls not only short-term cell functions such as contraction, secretion, exocytosis, and sensory signal transduction, but also long-term responses such as cell growth,

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proliferation, and cell death. The incentive mechanisms for Ca2+ signaling occurs through changes in the intracellular Ca2+ concentration ([Ca2+]i). The concentration at rest is around 100 nM, but on activation it can rise to roughly 1–10 µM. The diversity of Ca2+mediated effects is generated by the amplitude and spatiotemporal patterning of Ca2+ (Berridge et al., 2000).

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Two sources are available for elevating [Ca2+]i. First, the intracellular endoplasmic reticulum (ER) or the specific version found in muscle cells, the sarcoplasmic reticulum (SR), is a source of Ca2+. Ca2+ is released from the ER through the stimulation of G-protein-coupled receptors, which activate phospholipase (PL) C that generating inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). The IP3 receptor, which resides in the ER membrane, functions as a channel, releasing Ca2+ from the ER into the cytosol upon binding by IP3. Ca2+ release from the SR is mediated by direct coupling between a voltagegated Ca2+ channel (VGCC) in the muscle cell membrane and the SR ryanodine receptor, which functions as the Ca2+ release channel. Second, the extracellular milieu is a ready source of Ca2+, and several ion channels allow Ca2+ to enter the cell from the extracellular medium. In excitable cells including cardiomyocytes and vascular smooth muscle cells, VGCCs mediate a Ca2+ current on depolarization of the cell membrane above a threshold potential during an action potential. In cardiomyocytes, the Ca2+ entry is mediated partly through the action of the Na+/Ca2+ exchanger (NCX) running in “reverse mode.” Other Ca2+ entry channels include ligand-gated cation channels (LGCs), receptor-activated cation channels (RACs), and stretch-activated cation channels (SACs). Characteristically, LGCs are gated on binding of a ligand to the channel itself. RACs are gated when an agonist binds to a receptor distinct from the channel protein itself. Many RACs subtypes exist, with different Ca2+ selectivities, mechanisms of activation, and physiological functions. For instance, store-operated Ca2+ channels (SOCs), which are activated upon depletion of the intracellular Ca2+ store, and receptor-operated Ca2+ channels (ROCs), which are activated by DAG, are RACs. SACs are activated by mechanical stretching. Unlike the situation for VGCCs and the Na+/Ca2+ exchanger, the molecular identity of other Ca2+ entry channels has not been resolved completely. When asked about ion channels, most cardiologists will probably think of the voltage-gated Na+, K+, and Ca2+ channels first. Indeed, these channels have been studied extensively using electrophysiological, biochemical, and molecular–biological methods, and their channel modulators have been used as anti-arrhythmic agents or anti-hypertensive drugs. In recent years, however, the situation has started to change. Novel players regulating Ca2+ entry have recently been found in the still-growing family of so-called transient receptor potential (TRP) cation channels. The identification of mammalian TRP channels turned out to be a new starting point in the search for the molecular identification of Ca2+ entry pathways (SOCs, ROCs, LGCs, SACs, etc.) that contribute to the development of cardiovascular disease. This review discusses the expression and function of TRP channels in the cardiovascular system, the endogenous agonists and pathophysiological conditions that can modulate these channels, and the potential involvements of TRP channels in the pathogenesis of certain cardiovascular diseases. 2. The TRP superfamily Drosophila with mutations in a specific gene were found to have impaired vision due to the lack of a specific Ca2+ entry pathway into photoreceptors (Montell, 1997; Hardie, 2001; Minke & Cook, 2002). Due to the electrical phenotype, this gene was named trp for “transient receptor potential”, and the mammalian trp gene-related family was referred to as the TRP superfamily of membrane proteins that comprise cation channels. Twenty-eight mammalian members of the TRP family have been discovered. Based on homology, the following nomenclature for six different subfamilies has been accepted (Montell et al., 2002): TRPC (C for canonical), TRPV (V for vanilloid), TRPM (from the tumor suppressor melastatin), TRPP (P for polycystin), TRPML (ML for mucolipin), and TRPA (A for ankyrin). Transient receptor potential membrane proteins consist of six transmembrane spanning helices (TM1-6), cytoplasmic N- and Ctermini, and a pore region between TM5 and TM6 (Clapham et al.,

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2001; Montell et al., 2002). TM4 is not positively charged. The Ntermini of TRPV and TRPC, but not those of TRPM channels, contain multiple ankyrin binding repeats. The C-terminal part of TM6 in TRPC and TRPM channels includes the “TRP domain”, a conserved stretch of 25 amino acids starting with the nearly invariant “TRP box” that is missing in TRPV channels. In addition, all TRP channels have multiple regulatory and protein interaction sites. Multiple protein kinase A (PKA) and C (PKC) putative phosphorylation sites have been identified and partially tested for function. Phosphatidylinositide 3-kinase SH2recognition domains have also been identified in several TRP channels. TRP channels contribute to changes in [Ca2+]i by acting as Ca2+ entry channels in the plasma membrane directly or by changing membrane potentials, modulating the driving forces for the Ca2+ entry channels. All functionally characterized TRP channels are permeable to Ca2+ with the exceptions of TRPM4 and TRPM5, which are only permeable to monovalent cations. Most Ca2+-permeable TRP channels are only poorly selective for Ca2+, with a permeability ratio relative to Na+ (PCa/ PNa) in the range between 0.3 and 10. Exceptions are TRPV5 and TRPV6, two highly Ca2+-selective TRP channels for which PCa/PNa exceeds 100. TRP channels are gated by diverse stimuli that include the binding of intracellular and extracellular messengers, changes in temperature, and chemical or mechanical (osmotic) stress, and function as primary sensing molecules in the cell. Possible modes of TRP channel regulation involve activation via the phospholipase (PL)C-β and PLC-γ pathways, activation by lipids (DAG, arachidonic acid), Ca2+ depletion of ER Ca2+ stores, shear stress, and radicals. In addition, some TRP channels appear to be open constitutively. Functional TRP channels are homotetramers that are composed of the same TRP subunits or heterotetramers composed of different TRP subunits. Their ability to associate with a variety of partner proteins enables TRP channels to form different cation channels and regulate various cell functions in the cardiovascular system. However, the limited number of compounds that specifically block or activate respective TRP channels has impaired analysis of TRP channel function in primary cells. 3. TRP channels in the heart In the whole heart, the expression of several TRP channels (TRPC1, C3-7, TRPV2, -V4, TRPM4, -M5, -M7 and TRPP2/1) has been demonstrated in RT-PCR or biochemical studies (Table 1) (Inoue et al., 2006; Guinamard & Bois, 2007). 3.1. Regulatory role of TRPC channels in the development of cardiac hypertrophy Several pathological conditions, such as hypertension, aortic stenosis, and ischemia, increase the production of neurohumoral factors and mechanical stresses in the myocardium that subsequently activate intracellular signal transduction pathways, leading to cardiac hypertrophy (Ito et al., 1993; Frey et al., 2004). Intracellular Ca2+ acts as an inducer of these hypertrophic responses as well as being the fundamental regulator of actin–myosin cross-bridge interactions. [For more detailed reviews, see reference (Frey & Olson, 2003)]. However, the source of the Ca2+ responsible for the hypertrophic responses is still unknown. Research in this area has been hindered by the lack of obvious molecular identity. Previous studies have convincingly demonstrated the sufficiency of calcineurin to mediate cardiac hypertrophy and progressive heart failure (Molkentin et al., 1998). Calcineurin dephosphorylates transcription factors of the nuclear factor of the activated T cell (NFAT) family and translocates them into the nucleus, resulting in the activation of hypertrophic genes. Although the signaling pathway was first defined in lymphocytes, one fundamental question arises in relation to the processes of calcineurin activation in the myocardium. How does the cardiac myocyte distinguish between changes in Ca2+ that result in calcineurin activation versus the fluctuations in Ca2+ that occur during

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Table 1 Expression profile of TRP homologs in cardiovascular cells (modified from Yao and Garland, 2005 and Beech, 2005) TRPCI Endothelial cell Human coronary artery EC Cerebral artery EC Umbilical vein EC

C2 C3

C4

C5

C6

C7

V1

RT, ISH, IC RT, ISH, IC RT, ISH, IC RT, ISH, IC RT, ISH

RT, ISH, IC RT, WB

RT, ISH, IC RT, ISH, IC RT, ISH, IC RT, ISH, IC RT, ISH RT RT RT RT RT

RT, IC

RT, NB, WB

RT

RT, WB

RT

Bovine aortic EC

RT, WB, IC

RT

RT

Pulmonary artery EC Mouse aortic EC

RT

Pulmonary artery EC Rat pulmonary artery EC

RT RT

Pulmonary artery EC

RT

RT

RT

V3 V4

RT

RT

RT

RT

RT

RT, WB, IC RT RT RT RT, WB

RT RT

RT, IC RT

RT RT, WB

RT

RT

RT

RT RT

RT

RT

RT

RT, IC

RT

Portal vein SMC Rat aortic SMC Cerebral artery SMC

RT

RT

RT

RT, IC

RT, WB

RT, IC

RT

RT, WB, IC

Pulmonary artery SMC

RT

RT

RT

Rat

RT, WB

RT, WB

RT, WB

RT

RT

RT

RT

RT

NB

RT RT

Cardiomyocyte Human

RT RT, WB

RT

NB

RT

RT, WB

M3 M4 M5 M6 M7 M8

RT

RT NB, WB

Mouse

M1 M2

RT, IC

RT

RT, WB

P2

RT

RT

RT, WB

RT, WB

RT

RT, WB

RT

RT

RT RT

RT

RT RT

RT RT RT

RT, WB

RT

RT RT, WB

NB, ISH

RT, WB

NB

WB

IC indicates immunohistochemistry, ISH, in situ hybridization; NB; Northern blots; RT,RT-PCR;WB,Western blots.

RT

RT, WB

RT

NB

RT, WB

References Yip et al., 2004

RT RT RT

Smooth muscle cell Human coronary artery SMC Saphenous vein SMC Pulmonary artery SMC Mouse aortic SMC

P1

NB

RT

RT, WB

RT RT

RT RT

RT RT

RT RT

RT RT

RT, WB

RT

RT

RT

RT

RT

RT

RT, WB

RT

RT

RT

RT

RT

RT

RT

RT

(Golech et al., 2004; Yip et al., 2004) (Ahmmed et al., 2004; Foggensteiner et al., 2000; Groschner et al., 1998; Ibraghimov-Beskrovnaya et al., 1997; Jho et al., 2005; Kohler et al., 2001; Paria et al., 2003; Paria et al., 2004) (Brough et al., 2001; Fantozzi et al., 2003; Hecquet et al., 2008; Mehta et al., 2003; Moore et al., 1998; Paria et al., 2004) (Antoniotti et al., 2002; Chang et al., 1997; Garcia et al., 1997) Kamouchi et al. (1999) (Freichel et al., 2001; Nilius et al., 2003; Wissenbach et al., 2000) Tiruppathi et al. (2002) (McDaniel et al., 2001; Moore et al., 1998)

(Ohba et al., 2008; Takahashi et al., 2007a,b; Yip et al., 2004) Xu et al. (2006) (Jia et al., 2004; Kunichika et al., 2004a,b; Sweeney et al., 2002; Yu et al., 2004) (Dietrich et al., 2005; He et al., 2005, Muraki et al., 2003; Qian et al., 2003) Inoue et al. (2001) Inoue et al., 2006; Yang et al., 2006a,b) (Bergdahl et al., 2005; Inoue et al., 2006; Welsh, 2002; Xu et al., 2001) (Yang et al., 2006a,b; Yu et al., 2003)

(Bush et al., 2006; Chauvet et al., 2002; Guinamard et al., 2004; Kuwahara et al., 2006) (Demion et al., 2007; Iwata et al., 2003; Kuwahara et al., 2006; Ohba et al., 2006; Okada et al., 1999) (Bush et al., 2006; Guinamard, 2006; Nakayama et al., 2006 Ohba et al., 2007; Onohara et al., 2006; Satoh et al., 2007; Seth, 2004; Volk et al., 2003)

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RT, ISH, IC

V2

H. Watanabe et al. / Pharmacology & Therapeutics 118 (2008) 337–351

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Fig. 1. Proposed model of the development of cardiac hypertrophy via the TRPC/calcineurin/NFAT pathway. Hypertrophic stimuli by neurohormonal factors produce DAG and IP3. DAG activates ROCs directly. IP3 induces store depletion in SR/ER by Ca2+ release through the IP3 receptor. The subsequent store depletion opens SOC. Mechanical stress activates SACs. These Ca2+ entry channels (ROCs, SOCs and SACs), which consist mainly of TRPC channel homo/hetero-multimers in various combinations, induce a prolonged, low-amplitude Ca2+ rise. This sustained Ca2+ entry dominantly activates the calcineurin-NFAT pathway. The BNP gene is one of the downstream targets of the TRPC/calcineurin/NFAT pathway. NFAT increases TRPCs gene transcription, which enhances TRPC expressions. Upregulated TRPC channels further activate the calcineurin-NFAT pathway. This feed-forward mechanism causes long-termed hypertrophic changes in cardiac myocytes. Abbreviations: ET-1, Endothelin-1; ATII, angiotensin II; PE, phenylephrine; PLC, phospholipase C; DAG, diacylglycerol; IP3, inositol-1,4,5triphosphate; ROCs, receptor-operated Ca2+ channels; SOCs, store-operated Ca2+ channels; SACs, stretch-activated Ca2+ channels; SR/ER, sarcoplasmic reticulum/endplasmic reticulum; SERCA, sarcoplasmic/endplasmic reticulum Ca2+ ATPase; TRPC, transient receptor potential subfamily C; NFAT, nuclear factor of activated T cell; GATA, GATA-binding protein.

each cardiac cycle of contraction and relaxation? Studies in lymphocytes have demonstrated that NFAT remains in the nucleus only in response to prolonged, low-amplitude Ca2+ signals and is insensitive to transient, high-amplitude Ca2+ alterations (Timmerman et al., 1996; Dolmetsch et al., 1997; Crabtree, 1999). In cardiomyocytes, Ca2+ entry through a VGCC and the subsequent release of Ca2+ from the SR elicit a large Ca2+ increase, but the rise in Ca2+ is fully reversible over a time period of milliseconds. Neurohumoral factors [endothelin (ET) and angiotensin II (Ang II)], known as hypertrophic stimulants, bind G protein-coupled receptors and produce the secondary messengers IP3 and DAG. DAG activates ROCs, while IP3 induces Ca2+ release from the SR, producing a transient increase in [Ca2+]i. The subsequent depletion of Ca2+ stores triggers the opening of SOCs in the plasma membrane and causes the so-called store-operated Ca2+ entry (SOCE), which elicits a sustained increase in [Ca2+]i. A recent study showed that SOCE contributes to NFAT nuclear translocation and cardiac hypertrophy (Hunton et al., 2002), but the molecular composition of SOCs in cardiomyocytes remains unclear. Some TRP channels are the best potential candidates for SOCs and ROCs. Indeed, the involvement of TRPC1 in SOCE and subsequent NFAT activation has been demonstrated in B lymphocytes (Mori et al., 2002). Recently, several studies have reported the involvement of TRPC channels in cardiac hypertrophy. Spatial segregation of increased [Ca2+]i initiated by TRPC channels may contribute to the activation of the calcineurin/NFAT pathway in cardiac myocytes. Bush et al. showed that TRPC3 is upregulated in several animal models of cardiac hypertrophy, including cultured neonatal rat ventricular myocytes, thoracic aorta banded rats and spontaneous hypertensive heart failure rats, and that the TRPC3 promotes cardiomyocyte hypertrophy (Bush et al., 2006). Nakayama et al. reported the phenotype of cardiac-specific TRPC3 transgenic mice. Myocytes isolated from these mice exhibited an enhanced SOCE response, and TRPC3 transgenic mice showed increased calcineurin-NFAT activation in vivo, cardiomyopathy, and augmented hypertrophy after neuroendocrine agonist or pressure-overload stimu-

lation (Nakayama et al., 2006). Kuwahara et al. stated that TRPC6 is upregulated in models of cardiac hypertrophy, but siRNA knock down of TRPC6 reduced hypertrophic signaling induced by phenylephrine and ET-1(Kuwahara et al., 2006). TRPC6 transgenic mice exhibited increased NFAT activity and cardiomyopathy (Kuwahara et al., 2006). Onohara et al. showed that siRNA-mediated knockdown of TRPC3 or TRPC6 attenuates Ang II-induced NFAT activation and cardiomyocyte hypertrophy (Onohara et al., 2006). In addition to TRPC3 and TRPC6, we showed that TRPC1 functions as a SOC in cardiomyocytes and that its upregulation is involved in the development of cardiac hypertrophy induced by ET-1, Ang II or pressure overload (Ohba et al., 2007). Although differences exist in the TRPC isoforms among these studies, each finding may not preclude a role for other TRPCs in mediating hypertrophic responses because both SOCs and ROCs are thought to be heteromultimers consisting of different TRPC subunits. Interestingly, TRPC1, TRPC3 and TRPC6 have conserved NFAT consensus sites in the promoter (Bush et al., 2006; Kuwahara et al., 2006; Ohba et al., 2007). Conceivably, once activated, NFAT might stimulate TRPC channels expression through a positive feedback mechanism. Since clinically important cardiac hypertrophy arises over the long term, this positive feedback mechanism could feasibly stimulate the development of cardiac hypertrophy (Fig. 1). In addition, we demonstrated that neuron-restrictive silencer factor, which represses the expression of multiple fetal cardiac genes (Kuwahara et al., 2003), regulates TRPC1 gene expression in the development of cardiac hypertrophy (Ohba et al., 2006). TRPC channels lack obvious voltage sensors in TM4, unlike the VGCCs. The amount of Ca2+ entry through a TRP channel is determined by the electrical driving force, which is greater in diastole than in systole during the cardiac cycle. Therefore, up-regulation of TRPCs in hypertrophied myocardium may contribute to diastolic dysfunction or arrhythmogenesis. Further studies to explore the mechanisms of TRPC channels regulation will lead to the development of novel therapeutic strategies to prevent cardiac hypertrophy.

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3.2. TRPC channels and failing myocardium

3.4. Involvement of TRP channels in pacemaking in the sinoatrial node

Altered intracellular Ca2+ handling contributes to impaired contractility in heart failure. [For more detailed reviews, see references (Prestle et al., 2003; Bers et al., 2006)]. In cardiac muscle, intracellular Ca2+ stores and the Ca2+ ATPase (SERCA2 isoform) in the SR play prominent roles in contractile activation and relaxation. Increased levels of NCX have been detected in conjunction with SERCA downregulation in failing hearts. In addition, an in vitro study using small interfering RNA against SERCA demonstrated that reduction of SERCA2 expression was associated with the up-regulation of TRPC4, TRPC5, and NCX, indicating that a deficiency in intracellular stores might be compensated for by Ca2+ entry through the plasma membrane (Seth et al., 2004). Indeed, induction of TRPC5 or TRPC6 expression is seen in the failing human heart (Bush et al., 2006; Kuwahara et al., 2006). The importance of this compensatory mechanism may be related to its general involvement in Ca2+ signaling mechanisms not only for excitation–contraction coupling but also for cardiac remodeling and hypertrophy. Myocardial apoptosis has been suggested to be an important process that contributes to the development of heart failure in both animal models and humans; hence, inhibition of apoptosis is a promising therapeutic option. The apoptotic process is evoked by various stimuli, including oxidative stress, pro-inflammatory cytokines, catecholamines, and Ang-II (Kang & Izumo, 2003). Intracellular Ca2+ elevation has been thought to be a key initiator of intracellular signaling of apoptosis (e.g., activation of Ca2+-dependent endogenous endonuclease). At the present time, the involvement of two TRP channels in myocardial apoptosis has been reported in an animal model. Activation of the TRPM2 channel and poly (ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death (Yang et al., 2006a, 2006b). The apoptotic component is caused by the activation of clotrimazole-sensitive, NAD + /ADP ribose/poly (ADP-ribose) polymerase (PARP)-dependent TRPM2 channels, which induces mitochondrial Na+ and Ca2+ overload, resulting in mitochondrial membrane disruption, cytochrome c release, and caspase 3-dependent chromatin condensation/fragmentation. It has also been reported that TRPC7 may be a key initiator linking AT1activation to myocardial apoptosis, thereby contributing to the process of heart failure (Satoh et al., 2007). Although these findings provide possible strategies for modulating cardiac apoptosis, further investigation is required to clarify the complex and intricate balance between cardiac apoptosis and heart failure.

Although growing evidence indicates that diastolic depolarization can be generated by an inward NCX current related to Ca2+-induced Ca2+ release from the SR (Vinogradova et al., 2005), whether SR Ca2+ release is essential for cardiac pacemaker function has remained debatable (Lipsius & Bers, 2003). Ju and Allen and colleagues have introduced the SOC current, which might be involved in pacemaking (Ju et al., 2007). They found that the SOC blocker SK&F-96356 slowed the firing rate and that pacemaker firing was further slowed when SR Ca2+ stores were depleted with cyclopiazonic acid. In addition, they demonstrated RT-PCR evidence of transcripts for six of the seven TRPC channels (the exception was TRPC5) in the sinoatrial node. Since TRPC proteins are considered to be a pivotal component for SOC (one exception to this is TRPC6), these studies raise the possibility that TRPC isoforms are responsible for SOC activity and contribute to pacemaker firing. Recently, the expression of TRPM4 was also demonstrated in mouse sinoatrial node cells (Demion et al., 2007). The functional property of a nonselective cation channel in mouse sinoatrial node cells shows the hallmarks of the TRPM4 channel. It is activated by a rise in [Ca2+]i and is voltage-dependent with a conductance of 20.9 ± 0.5 pS. It is equally permeable to Na+ and K+, but does not conduct Ca2+. These data suggest a Ca2+-activated nonselective cationic channel in mouse SAN cells corresponding to TRPM4. Although it is not known whether the Ca2+ level reached at the peak is sufficiently high to activate the TRPM4 channel, TRPM4 could be a new therapeutic target for controlling the heart rhythm.

3.3. Pathological role of TRP channels in the heart in muscular dystrophy Muscular dystrophies are disorders of progressive skeletal muscle degeneration. The most common X-linked recessive disease is Duchenne muscular dystrophy (DMD), which arises from defects in the dystrophin gene. Some DMD patients develop a dilated cardiomyopathy leading to heart failure. [For more detailed reviews, see references (Finsterer & Stollberger, 2003; Cohen & Muntoni, 2004).] So far, it is not known why the absence of the dystrophin protein induces cardiomyocyte degeneration leading to heart failure. In skeletal muscle, changes in Ca2+ handling are accepted as being involved in the pathogenic process. One study showed that a lack of dystrophin results in increased activity of SACs in skeletal muscle (Vandebrouck et al., 2001). The resulting increase in resting [Ca2+]i is thought to activate proteases and has been implicated in the pathogenesis of skeletal muscle damage in DMD. Therefore, SACs may play a role in the pathogenesis of the heart failure associated with DMD. It was recently shown that mdx mice express increased TRPC1 protein, which is a likely candidate protein for SACs (Williams & Allen, 2007). In addition, the increased expression of TRPV2 has been suggested to cause cardiac muscle degeneration in dystrophic cardiomyopathy (Iwata et al., 2003). These findings suggest that SACs, in particular TRPC1or TRPV2, play a role in the pathogenesis of the cardiomyopathy associated with DMD.

3.5. TRPM4 channel participates in the triggering of arrhythmias Cardiac arrhythmias, which occur in a wide variety of conditions when [Ca2+]i is elevated, have been attributed to the activation of a transient inward current. [For a more detailed review, see references (Janse, 2004; Guinamard et al., 2006a, 2006b)]. The transient inward current is the result of some different [Ca2+]i-sensitive currents, including a Ca2+-activated nonselective cationic current. Since the first single-channel measurements in cardiac cells revealing a Ca2+-activated nonselective cation channel (Colquhoun et al., 1981), considerable effort has been undertaken to identify molecular candidates for this channel. One recent study showed that this channel is likely a TRPM4 channel (Guinamard et al., 2006a, 2006b). In the heart, TRPM4 seems to be expressed more in atrial than in ventricular myocardium (Nilius & Vennekens, 2006). Functional characterization of a Ca2+-activated nonselective cation channel in human atrial cardiomyocytes using the patch-clamp technique showed (Guinamard et al., 2004) that the channel is equally permeable to Na+ and K+ but not permeable to Ca2+, and the 25-pS NSCCCa channel properties match those of the TRPM4 fingerprint very closely. These findings suggest that TRPM4 is a serious candidate supporting the delayed after-depolarizations observed under conditions of Ca2+ overload and could cause irregular electrical activity. A follow-up study by the same group demonstrated increased TRPM4 expression in cardiac hypertrophy using freshly isolated ventricular myocytes from spontaneously hypertensive rats (SHR)(Guinamard et al., 2006a, 2006b). The level of TRPM4 mRNA is much higher in SHR than in Wistar-Kyoto rats (WKY). The expression is functional as TRPM4 current is recordable in SHR but not in WKY cardiomyocytes. Therefore, TRPM4 could participate in some features of cardiac arrhythmias associated with cardiac hypertrophy. 3.6. TRPP2 channels and cardiac defects Mutations in either TRPP1 (PKD-1) or TRPP2 (PKD-2) genes lead to autosomal dominant polycystic kidney disease (ADPKD), which is characterized by the progressive development of large fluid-filled cysts in the kidney. [For reviews, see references (Gout et al., 2007; Rossetti &

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Harris, 2007)] TRPP2-deficient mice are known to have cardiac defects (Wu et al., 2000). Because TRPP2-like channels have been reported to exist within the heart (Volk et al., 2003) and the expression pattern of TRPP2 during heart development is relatively stable (Chauvet et al., 2002), TRPP2 channels might be involved in the normal development of the interventricular and interatrial septa. Inactivation of the gene encoding the bone morphogenetic protein-1-related metalloprotease tolloid-like 1 produces a cardiac-restricted phenotype (Clark et al., 1999) that resembles the phenotype of TRPP2−/− mice. Tolloid-like 1 is thought to affect heart morphogenesis through a pathway that involves TGF-like molecules and matrix deposition, which are factors that may be involved in a potential “TRPP2 pathway” in the heart. However, a detailed mechanism remains elusive. Further studies are required to clarify the physiological importance of TRPP2 and to determine the role of TRPP2 in cardiac development. Interestingly, the cardiac phenotypes found in TRPP2−/− mice were not seen in TRPP1del34/del34 mice. It is possible that TRPP2 activity in the developing heart involves interaction with cardiacspecific partners distinct from TRPP1. 3.7. TRPV1 channel in cardiac sensory neurons Chest pain is a hallmark of myocardial ischemia, but its underlying signaling mechanisms remain poorly understood. The cardiac sensory afferents and their cell bodies in the dorsal root ganglion are generally considered the essential pathways for the transmission of cardiac nociception to the dorsal horn of the upper thoracic spinal cord. Increased production of bradykinin during myocardial ischemia has been proposed to contribute to the excitation of cardiac nociceptors in cardiac sympathetic sensory neurons that trigger chest pain [for reviews, see reference (Longhurst et al., 2001)). Recently, Pan et al. provided new evidence that iodoresiniferatoxin, a selective antagonist of TRPV1, attenuates both bradykinin- and ischemia-induced firing of cardiac spinal afferent nerves (Pan & Chen, 2004). Therefore, it is likely that ischemic stimulation of cardiac spinal afferent nerves is mediated through TRPV1. The TRPV1 on the cardiac sensory nerve may function as a molecular sensor to detect tissue ischemia and activate cardiac nociceptors. Blocking TRPV1 in cardiac sensory neurons may be an alternative intervention for the treatment of refractory ischemic chest pain that cannot be relieved by conventional therapies. 3.8. TRPC channels in cardiac fibroblasts Cardiac fibroblasts play a central role in maintaining the extracellular matrix in normal heart tissue and serve as mediators of inflammatory and fibrotic myocardial remodeling in injured hearts (see references Brown et al., 2005; Bujak & Frangogiannis, 2007). Growing evidence implicates cardiac fibrosis in the outcome of heart failure and incidence of atrial fibrillation (Brown et al., 2005). It has been known that natriuretic peptide C is thought to exert antifibrotic effects during heart failure (Horio et al., 2003). Recently, Rose et al. reported that cardiac fibroblasts express NSCC that are potently activated by natriuretic peptide C, in which TRPC2, TRPC3, and TRPC5 mRNA were expressed (Rose et al., 2007). In another study, ET-1induced myofibroblast formation was suppressed by overexpression of TRPC6, whereas it was enhanced by TRPC6 small interfering RNAs. Up-regulation of TRPC6 negatively regulates ET-1-induced cardiac myofibroblast formation and collagen synthesis through the activation of NFAT (Nishida et al., 2007). These studies point the way to future challenges in cardiac fibroblast biology and pharmacotherapy. 4. TRP channels in the vasculature The entry of Ca2+, Mg2+, and Na+ plays central roles in the function and survival of vascular smooth muscle cells (VSMCs). The entry pathways consist of highly Ca2+-selective channels (e.g., VGCCs) and poorly Ca2+-selective nonselective cation channels (NSCCs). In parti-

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cular, NSCCs are targets of excitatory agonists. Na+ entry through NSCCs causes depolarization and activates VGCCs, resulting in cell contraction (Walker et al., 2001). However, progress in understanding the entry pathway has been limited by a lack of identification of the genes underlying various NSCCs. Many endothelial cell functions depend on the entry of extracellular Ca2+, which is multimodally activated or modulated by receptor stimulation, temperature, mechanical stress, or lipid secondary messengers generated from various sources, and may be involved in both acute vasomotor control and long-term vascular remodeling. These Ca2+ entry pathways in VSMCs and endothelial cells, which are thought to be consistent with TRP channels, may play important roles in regulating the pulmonary and systemic circulation (Yang et al., 2006a, 2006b). Knowledge that TRP channels are relevant to vascular smooth muscle and endothelial cells in both their contractile and proliferative phenotypes should pave the way for a better understanding of vascular biology and provide a basis for the discovery of a new set of therapeutic agents targeted to vascular disease. The expression pattern of TRP channels in the vasculature has been described in peer-reviewed studies (Yao & Garland, 2005; Beech, 2005; Dietrich et al., 2006; Firth et al., 2007; Kwan et al., 2007). More than ten distinct TRP homologs (all of the TRPCs; TRPV1-V4; all of the TRPMs; and TRPP2/1) have been detected in VSMCs from various species using RT-PCR, Western blotting, and immunohistochemistry (see Table 1) (Beech, 2005; Inoue et al., 2006). At least 19 (all of the TRPCs; TRPV1, -V2, and -V4; all of the TRPMs except -M5; and TRPP2/1) are expressed in vascular endothelial cells (see Table 1) (Yao & Garland, 2005; Kwan et al., 2007). Both smooth muscle and endothelium are remarkably diverse, with major structural and functional heterogeneity apparent between organs, along vascular segments, and indeed, within immediately adjacent cells. Little is known about how this diversity is maintained and how sitespecific responses are determined. TRP channels are widely expressed in human vessels of all calibers, including medium-sized coronary arteries and cerebral arteries, smaller-sized resistance arteries, and vaso vasora (Yip et al., 2004). Moreover, the assembly of TRP multimers is not completely understood. In particular, the heteromeric assembly of distantly related TRP isoforms remains controversial. Multimerization of TRP species has emerged as a complex issue because both homo- and heteromeric assemblies appear possible and up to three isoforms may contribute to the formation of native pore complexes (Strubing et al., 2003). Functional heterogeneity in the vasculature may be partly linked to the diversity of heteromeric assemblies of TRP isoforms. 4.1. TRP channels and the growth of vascular smooth muscle cells 4.1.1. Functional role of TRP channels in vascular remodeling Studies have shown that the removal of extracellular Ca2+ or depletion of intracellularly stored Ca2+ in the SR significantly inhibits VSMCs growth (Gallois et al., 1998; Shimoda et al., 2000). Moreover, the resting [Ca2+]i has been reported to be much higher in proliferating cells than in growth-arrested cells (Golovina et al., 2001). These observations imply that constant Ca2+ entry, which can raise the cytoplasmic or nuclear Ca2+ concentration and refill Ca2+ in depleted SR, is necessary for VSMC growth. VSMC growth is one of the causes of vascular remodeling associated with the development of hypertension, atherosclerosis, and re-stenosis after balloon angioplasty [for reviews, see reference (Bochaton-Piallat & Gabbiani, 2005)], but its early signals are not completely understood. Therefore, regulating Ca2+ is a definite target for pharmacological and genetic modification of the vascular remodeling process. Our study using human coronary artery smooth muscle cells (hCASMCs), showed that Ang II and the subsequent NF-κB activation facilitates hCASMC growth through up-regulation of the TRPC1 channel and resultant increase in SOCE (Takahashi et al., 2007a, 2007b). This finding is supported by other reports that demonstrate up-regulation of the TRPC1 channel in human neointimal hyperplasia after vascular

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injury (Kumar et al., 2006), and studies that show that rat cerebrovascular injury by balloon dilatation enhances TRPC1 expression, which is correlated with cellular SOCE (Bergdahl et al., 2005). These studies suggest that TRPC1 forms SOCs which play a pivotal role in VSMC proliferation; however, the way in which cells are able to sense the depletion of Ca2+ stores remains unknown. The recent identification of stromal interaction molecule 1 (STIM1) has provided an important clue to this difficult question (Liou et al., 2005; Roos et al., 2005). STIM1 regulates SOCs by functioning as an ER Ca2+ sensor. We demonstrated that STIM1, together with TRPC1, is an essential component of SOCE in VSMCs and that it is involved in proliferation at least partly through cyclic AMP response element-binding protein (CREB) phosphorylation (Takahashi et al., 2007a, 2007b). Therefore, TRPC1 could be a definite target for pharmacological and genetic modification against vascular remodeling. Intracellular Mg2+ may influence blood pressure by modulating vascular tone and structure through its effects on numerous biochemical reactions that control vascular contraction/dilation and growth/apoptosis. In particular, low Mg2+ conditions contribute to increased vascular tone, oxidative stress, vascular remodeling, and increased blood pressure (Laurant et al., 1997). Accumulating evidence indicates reduced [Mg2+]i in vascular from experimental models of hypertension and essential hypertensive patients (Touyz, 2003). Although molecular mechanisms regulating VSMC Mg2+ remained unknown, recently, He et al. have demonstrated that TRPM7 channels act as a functionally important regulator of Mg2+ homeostasis and Ang II-induced growth in human VSMCs (He et al., 2005). Down-regulation of TRPM7, but not TRPM6, may play a role in the altered Mg2+ homeostasis in VSMCs, as seen in spontaneously hypertensive rats (Touyz et al., 2006). TRPM7 may be a functionally important regulator of Mg2+ homeostasis and growth in VSMCs. Sphingolipids act as both first and second messengers in a variety of signaling pathways. The sphingolipid metabolite sphingosine-1-phospate (S1P) is important for directed cell movement. Xu et al. showed that S1P activates a membrane current conducted by ion channels formed by TRPC5, increasing [Ca2+]i (Xu et al., 2006). In addition, using smooth muscle cells from the saphenous veins of patients undergoing coronary artery surgery, they showed that antibody-based inhibition of TRPC5 prevents S1P-induced motility of cultured smooth muscle cells. This study suggests that the sphingolipids and TRP channels are functionally linked in VSMCs, and that S1P activates TRPC5, controlling VSMC motility (Xu et al., 2006). 4.1.2. TRP channels and idiopathic pulmonary hypertension Idiopathic pulmonary arterial hypertension (IPAH) is a progressive, fatal disease. Pulmonary vascular medial hypertrophy caused by excessive pulmonary artery smooth muscle cell (PASMC) proliferation is a major cause of the elevated pulmonary vascular resistance in patients with IPAH [for more detailed reviews, see reference (Raiesdana & Loscalzo, 2006)]. Increased Ca2+ entry is an important stimulus for PASMC proliferation. An in vitro study indicated that platelet-derived growth factor (PDGF)-mediated PASMC proliferation is associated with c-Jun/STAT3-induced up-regulation of TRPC6 expression. Up-regulation of TRPC6 has also been shown in ET-1-treated PASMC (Kunichika et al., 2004a, 2004b). The resultant increase in SOCE raises [Ca2+]i, facilitates the return of Ca2+ to the SR, and enhances PASMC growth (Yu et al., 2003). The expression of TRPC6 protein in PASMCs is closely correlated with the expression of Ki67, suggesting that TRPC6 expression is involved in the transition of PASMCs from the quiescent phase to mitosis. Moreover, in PASMCs from patients with IPAH, the expression of TRPC3 and -6 mRNA and protein is much higher than in PASMCs from patients with normotensive or secondary pulmonary hypertension. Inhibition of TRPC6 expression with small interfering RNA against TRPC6 markedly attenuates IPAH-PASMC proliferation. Bosentan, a dual ET receptor blocker, has been used to treat IPAH clinically. An in vitro study has shown that bosentan inhibits TRPC6 expression induced by ET-1 and

PDGF, possibly independent of ET receptor blockade, and results in the inhibition of PASMC growth (Kunichika et al., 2004a, 2004b). Combined, these findings suggest that increased TRPC6 expression may be involved in the overgrowth of PASMCs in patients with IPAH (Yu et al., 2004). Meanwhile, in human PASMCs from non-pulmonary hypertension, TRPC1 seems to play a critical role in PASMC proliferation by regulating SOCE and [Ca2+]i (Golovina et al., 2001; Sweeney et al., 2002). Caveolae are cholesterol-rich invaginations of the plasma membrane that have been implicated in a variety of cellular functions. Since caveolin-1 facilitates caveolae formation and governs the localization of TRPC channels, the elevated TRPC expression in human PASMCs may be related to caveolin-1 expression. In a recent study, treatment of IPAH-PASMC with agents that deplete membrane cholesterol (methyl-beta-cyclodextrin or lovastatin) disrupted caveolae, attenuated SOCE, and inhibited DNA synthesis of IPAH-PASMC, implying that increased expression of caveolin-1 and caveolae contributes to the pathophysiology of IPAH. Treatments that downregulate caveolin/ caveolae expression with cholesterol-lowering drugs may prove to be novel therapeutic approaches for preventing the development of IPAH (Patel et al., 2007). In the treatment of IPAH, prostacyclin and its analogs presumably act via increases in cellular cAMP, thereby leading to pulmonary arterial vasodilatation and antiproliferative effects on PASMCs (Wharton et al., 2000). However, the therapeutic effects of prostacyclin and other cAMPstimulating agents on IPAH differ in different patients. Zhang et al. showed that a prolonged increase in cellular cAMP enhances TRPC3 expression and results in increase of Ca2+ entry through these channels in IPAH PASMC. They suggested that the diverse effects of cAMP may contribute to the inefficiency of cAMP-generating generating agents in the treatment of IPAH (Zhang et al., 2007). 4.2. TRP channels and vasoconstriction A key process involved in vasoconstriction is VSMC contraction, which is caused by Ca2+ entry through Ca2+ permeable channels. Various stimuli induce vasoconstriction including chemical and mechanical stimuli and endogenous substances, and causes vascular diseases. Here we focus on the involvement of TRP channels in various vasoconstrictive diseases. 4.2.1. TRP channels and agonist-induced vasoconstriction Membrane depolarization in arterial SMCs opens VGCCs, and their steep voltage dependence means that small changes in membrane potential dramatically affect the probability of channel opening, Ca2+ entry, and vascular tone. Various agonists (norepinephrine, vasopressin, ET, Ang II, and UTP) that bind to receptors on the SMC plasma membrane and activate the PLC-IP3 signal transduction pathway depolarize and constrict arterial SMCs. An unresolved issue in vascular biology is the identification and characterization of the membrane channels responsible for agonist-induced depolarization of arterial SMCs. The recent identification of TRP channels in native VSMCs raised the interesting possibility that TRPC channels mediate agonist-induced membrane depolarization. Members of this family are found in many different tissue types, including vascular cells. Specifically, TRPC1, TRPC3, and TRPC6 are found in the rat aorta (Facemire et al., 2004) and mouse portal veins (Inoue et al., 2001). TRPC1 and TRPC6 are expressed in A7r5 aortic SMCs (Jung et al., 2002; Brueggemann et al., 2006), while TRPC3 and TRPC6 are detected in rat cerebral arteries (Welsh et al., 2002). TRPC6 channels were reported to be the essential component of α1adrenoceptor activated-NSCC, which may serve as a store depletionindependent Ca 2+ entry pathway in rabbit portal vein SMCs during increased sympathetic activity (Inoue et al., 2001). In addition, TRPC6 channels were found to be involved in the vasopressin-activated cation channel in A7r5 aortic SMCs (Jung et al., 2002). In experiments using a TRPC6-deficient mouse model, constitutively active TRPC3-

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type channels were up regulated; however, these mice had elevated blood pressure and enhanced agonist-induced contractility of isolated aortic rings, as well as the cerebral arteries (Dietrich et al., 2005). The report suggested that TRPC3 and TRPC6 are not interchangeable functionally, and that TRPC6 is an essential component of ROCs in VSMCs. However, several studies have described the involvement of other TRP channels in agonist-induced vasoconstriction. Antisense oligodeoxynucleotide suppression of TRPC3, but not TRPC6, expression attenuates UTP-induced depolarization and constriction of rat cerebral arteries, and abolishes a UTP-activated ion current in isolated arterial SMCs (Reading et al., 2005). Both Ang II and ET-1 are known to be potent vasoconstrictors with important roles in controlling blood pressure. Saleh et al. reported that low concentrations of Ang II (1 nM) activates TRPC6 (and possibly TRPC1) but higher concentrations of Ang II (100 nM) stimulates only TRPC1 in mesenteric artery myocytes (Saleh et al., 2006). ET-1 produces an increase in [Ca2+]i, which is essential for ET-1-induced vasoconstriction (Miwa et al., 2005). The majority of the contractile response is mediated by the Ca2+ entry, but this does not involve classic VGCCs (Miwa et al., 2005). ET-1 activates a Ca2+-permeable cation channel with TRPC7, possibly as a heterotetramer with TRPC3 in rabbit coronary artery myocytes (PeppiattWildman et al., 2007). Another group has reported that cholesterol depletion affects the caveolar localization of TRPC1 and impairs vascular reactivity to ET-1 by reducing SOC entry dependent on TRPC1 (Bergdahl et al., 2003). In addition, in PASMCs, SOCE through TRP channels has been shown to play an important role in agonist-mediated PA contraction (McDaniel et al., 2001). Overexpression of TRPC1 in PASMCs enhances pulmonary vasoconstriction induced by SOCE (Kunichika et al., 2004a, 2004b). Taken together, growing evidence confirms the involvement of TRP channels in agonist-induced vasoconstriction. The differential activation of these TRP channels by various excitatory stimuli could have important implications for the development of new therapeutic strategies targeted to specific vasoconstrictor mechanisms in vascular disease. 4.2.2. Involvement of TRPC channels in cerebral vasospasm after aneurysmal subarachnoid hemorrhage Cerebral vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH). It is characterized by sustained constriction of the cerebral arteries, and VGCC antagonists are relatively less effective [for more detailed reviews, see reference (Rothoerl & Ringel, 2007)]. Several agents have been suggested as being responsible; among these agents, ET-1 is perhaps the most prominent given its ability to elicit powerful constriction of cerebral arteries. Recently, a novel mechanism of ET-1-induced vasospasm after SAH was proposed (Xie et al., 2007). Studies in a dog model of SAH and vasospasm have suggested that ET-1 significantly increases Ca2+ entry mediated by TRPC1 and TRPC4 or their heteromultimers in SMCs, which promotes the development of vasospasm after SAH. Manipulation of these TRPC isoforms may be a novel method for inhibiting vasospasm after SAH. 4.2.3. TRP channels control arterial myogenic tone Elevation of intravascular pressure causes depolarization and constriction (myogenic tone) of small arteries and arterioles, and this response is a key element in blood flow regulation. In particular, local control of cerebral blood flow is regulated in part through myogenic constriction of resistance arteries [for more detailed review, see reference (Panerai, 2008)]. This response requires Ca2+ entry via VGCCs secondary to SMC depolarization. A key question remains: at a molecular level, how is a change in intraluminal pressure coupled to a change in VSMC membrane potential? Recently, the TRPC6 or TRPM4 channels have each been proposed to play a critical role in the control of cerebral artery myogenic tone. Antisense oligodeoxynucleotides to TRPC6 decrease TRPC6 protein expression and greatly attenuate

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arterial smooth muscle depolarization and constriction caused by elevated pressure in intact cerebral arteries (Welsh et al., 2002). In vivo suppression of TRPM4 by infusing antisense oligodeoxynucleotides into the cerebral spinal fluid of Sprague-Dawley rats demonstrated that TRPM4 channels are major contributors to myogenic constriction and cerebral blood flow autoregulation in cerebral arteries (Reading & Brayden, 2007). A prior study demonstrated that intraluminal pressure can induce PKC translocation to the smooth muscle plasma membrane, suggesting that PKC activity is elevated by increasing the perfusion pressure. Earley et al. suggested that PKCdependent regulation of TRPM4 activity contributes to the control of cerebral artery myogenic tone (Earley et al., 2004; Earley et al., 2007). In addition to TRPC6 and TRPM4, the involvement of TRPV1 in myogenic constriction has been described in rat mesenteric arteries (Scotland et al., 2004). Scotland et al. showed that the elevation of intraluminal pressure is associated with the generation of 20hydroxyeicosatetraenoic acid, which in turn activates TRPV1 on Cfiber nerve endings resulting in the depolarization of nerves and consequent vasoactive neuropeptide release. Although other TRP channels, notably TRPC1 (Maroto et al., 2005), TRPV2 (Muraki et al., 2003) and TRPA1 (Corey et al., 2004) can also be mechanically activated, their roles in the control of VSMCs myogenic tone are still elusive. 4.2.4. TRP channels and hypoxic pulmonary vasoconstriction Regional alveolar hypoxia causes local vasoconstriction in the lung. This acute regional hypoxic pulmonary vasoconstriction is necessary to maintain optimized gas exchange by directing blood flow from poorly ventilated to well ventilated areas of the lung (Weissmann et al., 2006a, 2006b). However, the underlying oxygen sensing and signal transduction mechanisms of the acute vasoconstriction are largely unknown. A rise of [Ca2+]i in PASMCs has been suggested to be the key event in these processes (Weigand et al., 2005). Recently, TRPC6-deficient mice have been shown to lack acute hypoxic pulmonary vasoconstriction. The data suggest that TRPC6 plays an indispensable role in acute hypoxic pulmonary vasoconstriction (Weissmann et al., 2006a, 2006b). Therefore, manipulation of TRPC6 function may offer a therapeutic strategy for controlling pulmonary hemodynamics and gas exchange. Chronic hypoxia as occurs in ventilatory disorders induces lung vascular remodeling, pulmonary hypertension, and Cor pulmonale. The involvement of TRPCs is also suggested in chronic hypoxic pulmonary hypertension. In hypoxic pulmonary arteries, TRPC1 and TRPC6 expression increases two- to threefold. This is accompanied by significant increases in basal and store- and receptor-operated Ca2+ entries that contribute to the enhanced vascular tone in hypoxic pulmonary hypertension (Lin et al., 2004). Moreover, Wang et al. revealed that increased expression of TRPC1 and TRPC6 in PASMCs during chronic hypoxia is mediated by the ubiquitous oxygensensitive transcription factor hypoxia-inducible factor 1 (HIF-1) (Wang et al., 2006). The linkage between HIF-1 activity and TRPC expression suggests that the increased expression of TRPC channels under chronic hypoxia actually may contribute to the overall sequence of events leading to secondary pulmonary hypertension. 4.2.5. TRP channels and normoxic contraction of the ductus arteriosus At birth, the increase in oxygen causes contraction of the ductus arteriosus (DA), while premature neonates have a high incidence of persistent patency of the ductus. Continued patency results in a reversed shunt with a high flow of blood from the aorta to the pulmonary arteries, which may lead to heart failure and pulmonary hypertension. Normoxic inhibition of potassium channels in the SMCs of the ductus wall (DASMCs) leads to membrane depolarization and Ca2+ entry through VGCCs. However, studies have shown that substantial normoxic contraction remains after inhibition of this pathway, indicating the contribution of additional mechanisms. Recently, the involvement of SOCE in normoxic contraction of the DA has been suggested (Hong et al.,

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2006). Expressions of the TRPC1, TRPC3, TRPC4, and TRPC6 genes in the DA was demonstrated using RT-PCR. The SOC current in DASMCs has been found to be enhanced markedly by normoxia and correlated with functional ring studies and the expression of TRPC channels in the DA (Hong et al., 2006). Further understanding of the mechanisms for normoxic contraction of the DA will permit the development of pharmacological therapy to close the patent DA. 4.3. Vascular complications in autosomal-dominant polycystic kidney disease (ADPKD) Mutations in two disease-causing genes, PKD1 and PKD2, account for nearly all cases of autosomal dominant polycystic kidney disease (ADPKD). The respective gene products of PKD1 and PKD2 are called TRPP1 and TRPP2, or polycystin 1 and polycystin 2, or PKD1 and PKD2. TRPP1 and TRPP2 are thought to function together as part of a multiprotein receptor/ion-channel complex, or independently, and may be involved in transducing Ca2+ dependent mechanosensitive signals in renal epithelial cells and endodermally derived cells (Delmas, 2005). Cystic tissue is assumed to lack functional TRPP1/TRPP2, which acts as a negative regulator of cell growth (Li et al., 2005). In addition to the main feature of bilateral progressive cystic dilation of the renal tubules, ADPKD is a systemic disorder associated with fatal vascular complications, including ruptured intracerebral aneurysms [for reviews, see reference (Gibbs et al., 2004)]. Mammalian PKD1 and PKD2 are expressed in VSMCs. The two-hit hypothesis (both alleles mutated) is often used to explain the manifestation of ADPKD later in life even though the mutation is present at birth. In cystogenesis, “hit” is congenital (in either the PKD1 or PKD2 genes) and the subsequent “hit” occurs later in life as the cells grow and divide (Smyth et al., 2003). Meanwhile, haplo-insufficiency (gene dosage effect) may be at play for the cardiovascular pathology of TRPP1/TRPP2. Haplo-insufficiency of human TRPP2 function alters [Ca2+]i regulation and leads to decreased VSMC contractility (Qian et al., 2003). Contractility of VSMCs is involved not only in regulating vessel diameters but also in maintaining vascular structural and functional integrity. In the stroke-prone spontaneously hypertensive rat, for example, the basilar artery is shown reduced contractility and altered structure including regions of SMC disorganization (Arribas et al., 1996; Arribas et al., 1999). Weakened VSMCs of blood vessel walls have been shown to become apoptotic under fluid mechanical stress, resulting in vascular leakage and aneurysms (Wernig & Xu, 2002). Pkd2+/− VSMCs have also elevated cAMP levels. The [Ca2+]i reduction and cAMP accumulation can cause an increase in both cellular proliferation and apoptosis, resembling Pkd mutant phenotype (Kip et al., 2005). These mechanisms may partly contribute to the development of a variety of vascular complications such as hypertension and aneurysms in patients with ADPKD (Gao et al., 2004). Moreover, vascular fragility and leakage have been reported in PKD1−/−and PKD2−/− mouse models (Wu et al., 2000), and disruption of the negative regulation of SMC growth may be involved in vascular complications in ADPKD. TRPP1/TRPP2 may be cell-adhesion receptor complexes that link ubiquitous extracellular matrix components to the cell cytoskeleton. Furthermore, TRPP1 contains several so-called Ig-like PKD motifs that provide Ca2+-dependent homophilic interaction between TRPP1 proteins, probably from different cells, including endothelial cells and VSMCs. Stable cell–cell adhesion is needed to maintain the structural integrity of mature tissues. Disruption of such interactions may also be at play in the pathogenesis of intracranial aneurysms associated with ADPKD (Bichet et al., 2006). 4.4. TRPV1 channel in perivascular sensory nerves Anandamide, an endogenous lipid cannabinoid (CB), causes vasodilatation, bradycardia, and hypotension in animals and has

been implicated in the pathophysiology of endotoxic, hemorrhagic, and cardiogenic shock [for reviews see reference (Mendizabal & AdlerGraschinsky, 2003)]. Its action is mediated by the activation of CB receptors and TRPV4 located on vessel walls and TRPV1 located on sensory peptidergic nerve endings within the external layers of vessel walls. Anandamide-induced activation of TRPV1 on perivascular sensory nerves causes the release of calcitonin gene-related peptide (CGRP) and substance P and results in vasodilatation (Zygmunt et al., 1999). Recent evidence implicates TRPV1 on sensory C-fibers in cardioprotection. Wang et al. found that the post-ischemic recovery of various hemodynamic parameters was impaired in TRPV1−/− compared with wild-type mice (Wang & Wang, 2005). Sexton et al. have showed that myocardial ischemia generates 12-lipoxygenase-derived eicosanoids which protect against myocardial ischemia/reperfusion injury via activation of neuronal TRPV1 and the subsequent release of substance P and CGRP (Sexton et al., 2007). These results demonstrate a mechanism limiting endogenous damage, the targeting of which may prove useful in treating myocardial ischemia (Sexton et al., 2007). Interestingly, TRPV1 expression and function are impaired in Dahl salt-sensitive hypertensive rats (Wang & Wang, 2006). By contrast, the TRPV1 receptor is activated and its expression upregulated in Dahl saltresistant rats on a high-salt diet, which acts to prevent salt-induced increases in blood pressure by causing CGRP release. It is conceivable that the susceptibility of Dahl salt-sensitive rats to hypertension may be attributed, at least in part, to the lack of an adequate counterregulatory action from sensory nerves (Wang & Wang, 2006). 4.5. TRP channels and endothelium-dependent vasodilatation In response to vasoactive factors or shear stress, sustained Ca2+ entry into endothelial cells contributes to the increase in [Ca2+]i that is necessary for the synthesis and release of vasoactive compounds such as nitric oxide and prostaglandins [for reviews, see reference (Nilius & Droogmans, 2001)]. Several studies have demonstrated that vasoactive agonists can moderate endothelial [Ca2+]i levels via TRP channels. For instance, analysis of TRPC4−/− mouse aortic endothelial cells showed that these cells lack SOCs, and acetylcholine-induced Ca2+ entry is reduced markedly, resulting in a significant decrease in endothelium-dependent, NO-mediated vasorelaxation of blood vessels (Freichel et al., 2001). TRPC4-mediated SOCE likely requires the interaction of protein 4.1 with TRPC4 and the membrane skeleton (Cioffi et al., 2005). Recently, Murata et al. show that caveolin-1 deficiency impairs endothelial Ca2+ entry but not IP3 production, which results in a decrease in acetylcholine-induced prostacyclin release (Murata et al., 2007). Additionally, they showed that a channel complex consisting of caveolin-1, TRPC1, TRPC4, and the IP3 receptor may be crucial for agonist-induced Ca2+ entry into endothelial cells. In addition to TRPC channels, at least two other endothelial TRP channels, TRPV1 and TRPV4, may be important in endotheliumdependent vasodilatation. In the isolated rat mesenteric bed, the activation of TRPV1 by anandamide elicits the acute release of NO from endothelial cells, which is inhibited by TRPV1 antagonists (Poblete et al., 2005). In the rat carotid artery, a specific TRPV4 activator, 4αPDD, causes robust endothelium-dependent vasodilatation, which is suppressed by the TRPV4 blocker ruthenium red (Kohler et al., 2006). TRPV4 is activated by not only synthetic 4α-phorbols but also by mechanical stress, heat and inflammatory substances, such as anandamide, arachidonic acid, and epoxyeicosatrienoic acids (EETs), which can induce endothelium-dependent vasodilatation. Genetically encoded loss-of-function of TRPV4 results in a loss of shear stressinduced vasodilatation (Hartmannsgruber et al., 2007). In renal epithelial cells, TRPP1/P2 complex mediated flow-induced Ca2+ entry (Nauli et al., 2003). However, it is not clear whether endothelial TRPP1/ P2 have similar functions. We have proposed a novel mechanism for temperature dependent vasodilation in which endothelial TRPV4 can sense the change in

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temperature (N24 °C). The temperature dependence of TRPV4, at least in this range, implies that endothelial cells expressing TRPV4 should have constitutive open Ca2+ channels and an elevated [Ca2+]i. This property of the TRPV4 channel could have important consequences, e.g., for the steady-state production of NO. Cooling of peripheral blood vessels could induce vasoconstriction, while warming could induce vasodilatation (Minson et al., 2001). Therefore, it seems likely that TRPV4 could work as both a cold and a warm receptor in the endothelium. This idea may suggest a possible role of TRPV4 in Raynaud's phenomenon and in mediating inflammatory pathophysiology in fever by, for example, changing barrier properties that depend on Ca2+ influx (Watanabe et al., 2002). EDHF-mediated dilation exists in arteries and arterioles of multiple vascular beds. Several lines of evidence in diverse vascular beds have implicated endothelial epoxygenase products as the EDHF (Quilley & McGiff, 2000). As mentioned above, cytochrome P450-derived EETs have been shown to modulate the activity of TRPV4 channels in endothelial cells, which might contribute to the relaxant effects of their P450 epoxygenase-dependent metabolites on vascular tone (Watanabe et al., 2003; Vriens et al., 2005)(Vriens et al., 2004). In the rat middle cerebral artery, PLA2 is involved in endothelial Ca2+ influx through TRPV4 channels and resultant EDHF-mediated dilatation in cerebral arteries (Marrelli et al., 2007). In addition, Earley and colleagues identified a new putative mechanism that links endothelial epoxygenase products to local gating of large conductance Ca2+activated K+ channels by Ca2+ entry through TRPV4 in SMCs. TRPV4 forms a novel Ca2+ signaling complex with ryanodine receptors and large conductance Ca2+-activated K+ channels that elicits smooth muscle hyperpolarization and arterial dilation via Ca2+-induced Ca2+ release in response to an endothelial-derived factor (Earley et al., 2005). Combined, these findings suggest that TRPV4 channels are targets for endothelium-dependent vasodilatation by EDHF. Although these results suggest that TRPC1, -C4, -V1, and -V4 channels play an important role in endothelium-dependent vasorelaxation, it has not yet been demonstrated that altered function of these channels can impair endothelial function in humans directly. Nevertheless, these results may also lead to new treatments for various cardiovascular diseases, because endothelial dysfunction has been demonstrated to play a crucial role in the development and progression of chronic heart failure and ischemic heart disease. 4.6. TRP channels as an endothelial redox sensor Growing evidence suggests pivotal roles of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in human cardiovascular diseases (Lopez Farre & Casado, 2001). A typical target of ROS/RNS signaling is Ca2+ channels that mediate both long-term and acute endothelial responses to oxidative stress. Endothelial TRP channels may provide redox-sensitive cation conductance and may play a crucial role in oxidant-induced endothelial injury because excessive activation of these channels results in membrane depolarization and Ca2+ loading. Therefore, TRP channels are an attractive target for novel strategies aimed at preventing oxidative stress-related vascular dysfunction. The first evidence for the involvement of TRP channels in oxidantinduced endothelial injury was proposed by Groschner's group (Balzer et al., 1999). In porcine aortic endothelial cells, they showed that TRPC3/C4 heteromers are expressed endogenously and the endogenous redox-sensitive cation conductance is suppressed by dominant negative TRPC3 and TRPC4 mutants, suggesting the TRPC3/C4 heteromer as a possible candidate for a redox-sensitive cation channel (Poteser et al., 2006). However, the redox-sensitive channel observed in porcine aortic endothelium has distinctly different properties from the redox-sensitive cation conductance previously observed in calf aorta endothelial cells (Koliwad et al., 1996), suggesting speciesspecific molecular heterogeneity of endothelial redox-regulated

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cation channels. In addition, oxidative stress-induced disruption of caveolin 1-rich lipid raft domains, which interfere with functional TRPC channels, is likely to contribute to redox modulation of TRP proteins and to oxidative stress-induced changes in cellular Ca2+ signaling. Furthermore, recently, a close association between TRPM2 and H2O2-induced endothelial hyperpermeability has been reported (details are provided in the next section) (Hecquet et al., 2007). A recent notable finding is that TRP channels act as NO sensors in endothelial cells (Yoshida et al., 2006). NO has been shown to activate recombinant TRPC1, -C4, -C5, -V1, -V3, and -V4 of the TRPC and TRPV families via cysteine S-nitrosylation and to induce Ca2+ entry into cells. In particular, native TRPC5 channels are activated by nitrosylation via eNOS upon ATP receptor stimulation and elicit Ca2+ entry into endothelial cells. This finding implies that Ca2+ entry via nitrosylated TRPC5 mediates the positive feedback regulation of Ca2+-dependent NO production. Although the pathophysiological significance of nitrosylated TRP channels in endothelial cells is still elusive, this concept represents an approach that could affect future strategies for treating endothelial dysfunction. 4.7. TRPC channels regulate endothelial barrier function One of the important functions of the endothelium is to regulate the transport of liquids and solutes across the semi-permeable vascular endothelial barrier. Vascular inflammation induces endothelial cell contraction, cell shape changes, and consequently increased endothelial permeability [for more detailed reviews, see reference (Yuan, 2000)]. The changes are formed by gaps between endothelial cells and are elicited by Ca2+ entry. Some TRP channels, including TRPC1, -C4, and -C6, have been implicated in endothelial barrier dysfunction. Several studies have noted segmental vascular permeability regulation in the lungs. Depletion of stored Ca2+ activates a larger SOCE response in extra-alveolar (pulmonary artery; PAECs) compared to alveolar (pulmonary microvascular; PMVECs) endothelial cells (Wu et al., 2005). In the extra-alveolar system, store depletion and activation of Ca2+ entry via TRPC1, TRPC4, and TRPC6 has been suggested to disrupt the barrier (Tiruppathi et al., 2002; Paria et al., 2003, 2004; Singh et al., 2007). Specifically, the TRPC1-mediated signal may be associated with Rho activation or PKCα phosphorylation (Mehta et al., 2003; Ahmmed et al., 2004). Analysis of TRPC4−/− mice showed that impairment of SOCE in TRPC4−/− mice interferes with increases in lung vascular permeability. Therefore, TRPC4-dependent Ca2+ entry is a key determinant of increased permeability in the mouse pulmonary vasculature (Tiruppathi et al., 2002). Disruption of the alveolar septal barrier regulated by TRPV4 participation in the pathogenesis of acute lung injury and the resultant deleterious functional consequences, such as alveolar flooding and impairment of gas exchange, has been reported (Alvarez et al., 2006). Moreover, it has also been reported that high vascular pressure-induced alveolar flooding is attributable to P450 epoxygenase-dependent activation of TRPV4 (Jian et al., 2008). Collectively, the Ca2+ entry channels that increase permeability in extra-alveolar regions consist of TRPC channels, such as SOCs, whereas the activation of TRPV4 channels preferentially increases the permeability of the endothelial layer of primary gas-exchanging septal regions of the lung microvasculature. TRPV4 may be important in the treatment of acute lung injury and respiratory distress syndromes. In response to inflammatory agonists such as thrombin and bradykinin, Gq-TRPC6-mediated (Singh et al., 2007) and TRPC1/C4mediated Ca2+ entry (Cioffi & Stevens, 2006) were proposed to induce the resultant changes in endothelial cell shape. TNF-α-induced increased TRPC1 expression in HPAEC also resulted in marked endothelial barrier dysfunction in response to thrombin (Paria et al., 2003, 2004). Thrombin activation of protease-activated receptor-1 induces Ca2+ entry through store-operated channel TRPC1, which

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activates a feed-forward mechanism of TRPC1 expression via nuclear factor-kappa B activation in endothelial cells (Paria et al., 2006). ROS are known to be important mediators of vascular barrier dysfunction in settings such as acute respiratory distress syndrome, ischemia/reperfusion, and hypoxia. The molecular mechanisms of the oxidant-induced change in endothelial Ca2+ permeability remain unknown. Recently, in human pulmonary artery endothelial cells, TRPM2 was shown to mediate the H2O2-induced increase in endothelial permeability through the activation of Ca2+ entry (Hecquet et al., 2007). Vascular endothelial growth factor (VEGF) increases vascular permeability by stimulating endothelial Ca2+ entry. It seems likely that VEGF induces an endothelial ROC or SOC current in endothelial cells. In human microvascular endothelial cells, the VEGF-induced cation current has characteristics similar to those of VEGF-mediated TRPC currents in cells heterologously expressing VEGFR2 and TRPC3 or TRPC6 (Cheng et al., 2006). Another group also implicated TRPC1 in VEGF-induced vascular hyperpermeability. Human umbilical vein endothelial cells and human dermal microvascular endothelial cells showed that VEGF induced endothelial hyperpermeability via the PLCIP3 pathway, which activates extracellular Ca2+ entry via the plasmalemmal store-operated channel TRPC1. In addition, angiopoietin-1 exerts a protective effect on the vascular endothelial barrier, where the TRPC1-dependent Ca2+ influx induced by VEGF is suppressed by interfering with the interaction of IP3R with TRPC1, thereby negating the increase in endothelial permeability (Jho et al., 2005). 5. Conclusions TRP channels are expressed in nearly all cardiovascular tissues and consist of SOCs, ROCs, SACs, and LGCs Ca2+ entry channels. The functional significance of TRP channels is likely connected to a wide variety of gating stimuli, which induce Ca2+ entry by integrating multiple physical and chemical stimuli. Therefore, the involvement of TRP channels in cardiovascular disease is of specific interest as it offers the opportunity to interfere with Ca2+-dependent signaling processes in the cardiovascular system. Although, the roles of most of the TRP channels in cardiovascular diseases are largely unknown; undoubtedly, the studies linking the TRP channel function to disease will become an important priority in medical science. The polymodal function of TRP channels makes them especially attractive targets for future research in therapeutic strategies for treating cardiovascular diseases. Acknowledgment This research was sponsored by Grants-in-Aid for Scientific Research from JSPS, KAKENHI (H.W 19590849), Saito-ho-onkai Foundation (T.O), Japan Heart Foundation/Novartis Grant for Research Award on Molecular and Cellular Cardiology (H.W) and Grant from Mochida memorial foundation for medical and pharmaceutical research. We thank Mai Sawai for her assistance in the preparation of this review. References Ahmmed, G. U., Mehta, D., Vogel, S., Holinstat, M., Paria, B. C., Tiruppathi, C., et al. (2004). Protein kinase Calpha phosphorylates the TRPC1 channel and regulates storeoperated Ca2+ entry in endothelial cells. J Biol Chem 279, 20941−20949. Alvarez, D. F., King, J. A., Weber, D., Addison, E., Liedtke, W., & Townsley, M. I. (2006). Transient receptor potential vanilloid 4-mediated disruption of the alveolar septal barrier: a novel mechanism of acute lung injury. Circ Res 99, 988−995. Antoniotti, S., Lovisolo, D., Fiorio Pla, A., & Munaron, L. (2002). Expression and functional role of bTRPC1 channels in native endothelial cells. FEBS Lett 510, 189−195. Arribas, S. M., Gordon, J. F., Daly, C. J., Dominiczak, A. F., & McGrath, J. C. (1996). Confocal microscopic characterization of a lesion in a cerebral vessel of the stroke-prone spontaneously hypertensive rat. Stroke 27, 1118−1122 discussion 1122-1113. Arribas, S. M., Costa, R., Salomone, S., Morel, N., Godfraind, T., & McGrath, J. C. (1999). Functional reduction and associated cellular rearrangement in SHRSP rat basilar arteries are affected by salt load and calcium antagonist treatment. J Cereb Blood Flow Metab 19, 517−527.

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