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TRPV4 channels: physiological and pathological role in cardiovascular system

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Abstract

TRPV4 channels are non-selective cation channels permeable to Ca2+, Na+, and Mg2+ ions. Recently, TRPV4 channels have received considerable attention as these channels are widely expressed in the cardiovascular system including endothelial cells, cardiac fibroblasts, vascular smooth muscles, and peri-vascular nerves. Therefore, these channels possibly play a pivotal role in the maintenance of cardiovascular homeostasis. TRPV4 channels critically regulate flow-induced arteriogenesis, TGF-β1-induced differentiation of cardiac fibroblasts into myofibroblasts, and heart failure-induced pulmonary edema. These channels also mediate hypoxia-induced increase in proliferation and migration of pulmonary artery smooth muscle cells and progression of pulmonary hypertension. These channels also maintain flow-induced vasodilation and preserve vascular function by directly activating Ca2+-dependent KCa channels. Furthermore, these may also induce vasodilation and maintain blood pressure indirectly by evoking the release of NO, CGRP, and substance P. The present review discusses the evidences and the potential mechanisms implicated in diverse responses including arteriogenesis, cardiac remodeling, congestive heart failure-induced pulmonary edema, pulmonary hypertension, flow-induced dilation, regulation of blood pressure, and hypoxic preconditioning.

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Abbreviations

TRPV4:

Transient receptor potential

4α-PDD:

4α-phorbol 12, 13-didecanoate

TGF-β:

Transforming growth factor-β

col1A2:

Collagen, type I, alpha 2

α-SMA:

Alpha smooth muscle actin

NFAT:

Nuclear factor of activated T cells

MRTF-a:

Mechanosensitive transcription factor-a

EETs:

Epoxyeicosatrienoic acids

CYP450:

Cytochrome P450

L-NAME:

LG-nitro-l-arginine

L-NNA:

L-NG-nitroarginine

EDHF:

Endothelium-dependent hyperpolarization factor

NO:

Nitric oxide

eNOS:

Endothelial nitric oxide synthase

HUVECs:

Human umbilical vein endothelial cells

ROS:

Reactive oxygen species

HEK 293 cells:

Human embryonic kidney 293 cells

PKG:

Protein kinase G

PKC:

Protein kinase C

CGRP:

Calcitonin gene-related peptide

SP:

Substance P

MEF2C:

Myocyte enhancer factor 2C

CSEN:

Calsenilin

CaN:

Calcineurin

AP-1:

Activator protein-1

References

  1. Adapala RK, Thoppil RJ, Luther DJ, Paruchuri S, Meszaros JG, Chilian WM, Thodeti CK (2013) TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals. J Mol Cell Cardiol 54:45–52. doi:10.1016/j.yjmcc.2012.10.016

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Alessandri-Haber N, Dina OA, Joseph EK, Reichling D, Levine JD (2006) A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators. J Neurosci 26:3864–3874. doi:10.1523/JNEUROSCI.5385-05.2006

    Article  CAS  PubMed  Google Scholar 

  3. Arniges M, Fernández-Fernández JM, Albrecht N, Schaefer M, Valverde MA (2006) Human TRPV4 channel splice variants revealed a key role of ankyrin domains in multimerization and trafficking. J Biol Chem 281:1580–1586. doi:10.1074/jbc.M511456200

    Article  CAS  PubMed  Google Scholar 

  4. Bagher P, Beleznai T, Kansui Y, Mitchell R, Garland CJ, Dora KA (2012) Low intravascular pressure activates endothelial cell TRPV4 channels, local Ca2+ events, and IKCa channels, reducing arteriolar tone. Proc Natl Acad Sci USA 109:18174–18179. doi:10.1073/pnas.1211946109

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529. doi:10.1038/nrm1155

    Article  CAS  PubMed  Google Scholar 

  6. Berrout J, Mamenko M, Zaika OL, Chen L, Zang W, Pochynyuk O, O’Neil RG (2014) Emerging role of the calcium-activated, small conductance, SK3 K+ channel in distal tubule function: regulation by TRPV4. PLoS ONE 9:e95149. doi:10.1371/journal.pone.0095149

    Article  PubMed Central  PubMed  Google Scholar 

  7. Bubolz AH, Mendoza SA, Zheng X, Zinkevich NS, Li R, Gutterman DD, Zhang DX (2012) Activation of endothelial TRPV4 channels mediates flow-induced dilation in human coronary arterioles: role of Ca2+ entry and mitochondrial ROS signaling. Am J Physiol Heart Circ Physiol 302:H634–H642. doi:10.1152/ajpheart.00717.2011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Cabral PD, Garvin JL (2014) TRPV4 activation mediates flow-induced nitric oxide production in the rat thick ascending limb. Am J Physiol Renal Physiol 307:F666–F672. doi:10.1152/ajprenal.00619.2013

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Caligiuri SP, Aukema HM, Ravandi A, Guzman R, Dibrov E, Pierce GN (2014) Flaxseed consumption reduces blood pressure in patients with hypertension by altering circulating oxylipins via an α-linolenic acid-induced inhibition of soluble epoxide hydrolase. Hypertension 64:53–59. doi:10.1161/HYPERTENSIONAHA.114.03179

    Article  CAS  PubMed  Google Scholar 

  10. Cappelli H, Adapala R, Thoppil R, Ohanyan V, Luli J, Luther D, Paruchiri S, Meszaros JG, Chilian W, Thodeti C (2014) TRPV4 deficiency protects myocardium following myocardial infarction and transverse aortic constriction. FASEB J. doi:10.1096/fj.1530-6860

    Google Scholar 

  11. Carreño FR, Ji LL, Cunningham JT (2009) Altered central TRPV4 expression and lipid raft association related to inappropriate vasopressin secretion in cirrhotic rats. Am J Physiol Regul Integr Comp Physiol 296:R454–R466. doi:10.1152/ajpregu.90460.2008

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  12. Demicheva E, Hecker M, Korff T (2008) Stretch-induced activation of the transcription factor activator protein-1 controls monocyte chemoattractant protein-1 expression during arteriogenesis. Circ Res 103:477–484. doi:10.1161/CIRCRESAHA.108.177782

    Article  CAS  PubMed  Google Scholar 

  13. Earley S (2011) Endothelium-dependent cerebral artery dilation mediated by transient receptor potential and Ca2+-activated K+ channels. J Cardiovasc Pharmacol 57:148–153. doi:10.1097/FJC.0b013e3181f580d9

    Article  CAS  PubMed  Google Scholar 

  14. Earley S, Pauyo T, Drapp R, Tavares MJ, Liedtke W, Brayden JE (2009) TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure. Am J Physiol Heart Circ Physiol 297:H1096–H1102. doi:10.1152/ajpheart.00241.2009

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Feissner RF, Skalska J, Gaum WE, Sheu SS (2009) Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci (Landmark Ed) 14:1197–1218

    Article  CAS  Google Scholar 

  16. Félétou M, Vanhoutte PM (2006) Endothelium-derived hyperpolarizing factor: where are we now? Arterioscler Thromb Vasc Biol 26:1215–1225. doi:10.1161/01.ATV.0000217611.81085.c5

    Article  PubMed  CAS  Google Scholar 

  17. Filosa JA, Yao X, Rath G (2013) TRPV4 and the regulation of vascular tone. J Cardiovasc Pharmacol 61:113–119. doi:10.1097/FJC.0b013e318279ba42

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Fiorio Pla A, Ong HL, Cheng KT, Brossa A, Bussolati B, Lockwich T, Paria B, Munaron L, Ambudkar IS (2012) TRPV4 mediates tumor-derived endothelial cell migration via arachidonic acid-activated actin remodeling. Oncogene 31:200–212. doi:10.1038/onc.2011.231

    Article  CAS  PubMed  Google Scholar 

  19. Fleming I, Busse R (2003) Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am J Physiol Regul Integr Comp Physiol 284:R1–R12. doi:10.1152/ajpregu.00323.2002

    Article  CAS  PubMed  Google Scholar 

  20. Galvagni F, Orlandini M, Oliviero S (2013) Role of the AP-1 transcription factor FOSL1 in endothelial cells adhesion and migration. Cell Adh Migr 7:408–411. doi:10.4161/cam.25894

    Article  PubMed Central  PubMed  Google Scholar 

  21. Gao F, Wang DH (2010) Impairment in function and expression of transient receptor potential vanilloid type 4 in Dahl salt-sensitive rats: significance and mechanism. Hypertension 55(4):1018–1025. doi:10.1161/HYPERTENSIONAHA.109.147710

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Gao F, Wang DH (2010) Hypotension induced by activation of the transient receptor potential vanilloid 4 channels: role of Ca2+-activated K+ channels and sensory nerves. J Hypertens 28:102–110. doi:10.1097/HJH.0b013e328332b865

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Goedicke-Fritz S, Kaistha A, Kacik M, Markert S, Hofmeister A, Busch C, Bänfer S, Jacob R, Grgic I, Hoyer J (2015) Evidence for functional and dynamic microcompartmentation of Cav-1/TRPV4/KCa in caveolae of endothelial cells. Eur J Cell Biol. doi:10.1016/j.ejcb.2015.06.002

    PubMed  Google Scholar 

  24. Graier WF, Frieden M, Malli R (2007) Mitochondria and Ca2+ signaling: old guests, new functions. Pflugers Arch 455:375–396. doi:10.1007/s00424-007-0296-1

    Article  CAS  PubMed  Google Scholar 

  25. Grant AD, Cottrell GS, Amadesi S, Trevisani M, Nicoletti P, Materazzi S, Altier C, Cenac N, Zamponi GW, Bautista-Cruz F, Lopez CB, Joseph EK, Levine JD, Liedtke W, Vanner S, Vergnolle N, Geppetti P, Bunnett NW, Robbins N, Koch SE, Rubinstein JF (2007) Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. J Physiol 578:715–733. doi:10.1113/jphysiol.2006.121111

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Gross GJ, Gauthier KM, Moore J, Campbell WB, Falck JR, Nithipatikom K (2009) Evidence for role of epoxyeicosatrienoic acids in mediating ischemic preconditioning and postconditioning in dog. Am J Physiol Heart Circ Physiol 297:H47–H52. doi:10.1152/ajpheart.01084.2008

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Garcia-Elias A, Mrkonjić S, Jung C, Pardo-Pastor C, Vicente R, Valverde MA (2014) The TRPV4 channel. Handb Exp Pharmacol 222:293–319. doi:10.1007/978-3-642-54215-2_12

    Article  CAS  PubMed  Google Scholar 

  28. Hatano N, Itoh Y, Muraki K (2009) Cardiac fibroblasts have functional TRPV4 activated by 4α-phorbol 12, 13-didecanoate. Life Sci 85:808–814. doi:10.1016/j.lfs.2009.10.013

    Article  CAS  PubMed  Google Scholar 

  29. Heusch G, Libby P, Gersh B, Yellon D, Böhm M, Lopaschuk G, Opie L (2014) Cardiovascular remodelling in coronary artery disease and heart failure. Lancet 383:1933–1943. doi:10.1016/S0140-6736(14)60107-0

    Article  PubMed Central  PubMed  Google Scholar 

  30. Heusch G (2015) Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 116:674–699. doi:10.1161/CIRCRESAHA.116.305348

    Article  CAS  PubMed  Google Scholar 

  31. Hinz B, Gabbiani G (2010) Fibrosis: recent advances in myofibroblast biology and new therapeutic perspectives. Biol Rep 2:78. doi:10.3410/B2-78

    Google Scholar 

  32. Ho WS, Zheng X, Zhang DX (2015) Role of endothelial TRPV4 channels in vascular actions of the endocannabinoid, 2-arachidonoylglycerol. Br J Pharmacol. doi:10.1111/bph.13312

    Google Scholar 

  33. Inoue R, Jensen LJ, Shi J, Morita H, Nishida M, Honda A, Ito Y (2006) Transient receptor potential channels in cardiovascular function and disease. Circ Res 99:119–131. doi:10.1161/01.RES.0000233356.10630.8a

    Article  CAS  PubMed  Google Scholar 

  34. Ishikura T, Suzuki H, Shoguchi K, Koreeda Y, Aritomi T, Matsuura T, Yoshimura M, Ohkubo JI, Maruyama T, Kawasaki M, Ohnishi H, Sakai A, Mizuno A, Suzuki M, Ueta Y (2015) Possible involvement of TRPV1 and TRPV4 in nociceptive stimulation-induced nocifensive behavior and neuroendocrine response in mice. Brain Res Bull. doi:10.1016/j.brainresbull.2015.08.004

    PubMed  Google Scholar 

  35. Jäderstad J, Brismar H, Herlenius E (2010) Hypoxic preconditioning increases gap-junctional graft and host communication. NeuroReport 21:1126–1132. doi:10.1097/WNR.0b013e328340a77b

    Article  PubMed  Google Scholar 

  36. Jian MY, King JA, Al-Mehdi AB, Liedtke W, Townsley MI (2008) High vascular pressure-induced lung injury requires P450 epoxygenase-dependent activation of TRPV4. Am J Respir Cell Mol Biol 38:386–392. doi:10.1165/rcmb.2007-0192OC

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Jie P, Tian Y, Hong Z, Li L, Zhou L, Chen L, Chen L (2015) Blockage of transient receptor potential vanilloid 4 inhibits brain edema in middle cerebral artery occlusion mice. Front Cell Neurosci 9:141. doi:10.3389/fncel.2015.00141

    Article  PubMed Central  PubMed  Google Scholar 

  38. Kinsman B, Cowles J, Lay J, Simmonds SS, Browning KN, Stocker SD (2014) Osmoregulatory thirst in mice lacking the transient receptor potential vanilloid type 1 (TRPV1) and/or type 4 (TRPV4) receptor. Am J Physiol Regul Integr Comp Physiol 307:R1092–R1100. doi:10.1152/ajpregu.00102.2014

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Köhler R, Heyken WT, Heinau P, Schubert R, Si H, Kacik M, Busch C, Grgic I, Maier T, Hoyer J (2006) Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation. Arterioscler Thromb Vasc Biol 26:1495–1502. doi:10.1161/01.ATV.0000225698.36212.6a

    Article  PubMed  CAS  Google Scholar 

  40. Köttgen M, Buchholz B, Garcia-Gonzalez MA, Kotsis F, Fu X, Doerken M, Boehlke C, Steffl D, Tauber R, Wegierski T, Nitschke R, Suzuki M, Kramer-Zucker A, Germino GG, Watnick T, Prenen J, Nilius B, Kuehn EW, Walz G (2008) TRPP2 and TRPV4 form a polymodal sensory channel complex. J Cell Biol 182:437–447. doi:10.1083/jcb.200805124

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  41. Lee H, Iida T, Mizuno A, Suzuki M, Caterina MJ (2005) Altered thermal selection behavior in mice lacking transient receptor potential vanilloid 4. J Neurosci 25:1304–1310. doi:10.1523/JNEUROSCI.4745.04.2005

    Article  CAS  PubMed  Google Scholar 

  42. Lei L, Cao X, Yang F, Shi DJ, Tang YQ, Zheng J, Wang K (2013) A TRPV4 channel C-terminal folding recognition domain critical for trafficking and function. J Biol Chem 288:10427–10439. doi:10.1074/jbc.M113.457291

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Lin JH, Lou N, Kang N, Takano T, Hu F, Han X, Xu Q, Lovatt D, Torres A, Willecke K, Yang J, Kang J, Nedergaard M (2008) A central role of connexin 43 in hypoxic preconditioning. J Neurosci 28:681–695. doi:10.1523/JNEUROSCI.3827-07.2008

    Article  CAS  PubMed  Google Scholar 

  44. Liu Y, Bubolz AH, Mendoza S, Zhang DX, Gutterman DD (2011) H2O2 is the transferrable factor mediating flow-induced dilation in human coronary arterioles. Circ Res 108:566–573. doi:10.1161/CIRCRESAHA.110.237636

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Liu Y, Zhao H, Li H, Kalyanaraman B, Nicolosi AC, Gutterman DD (2003) Mitochondrial sources of H2O2 generation play a key role in flow-mediated dilation in human coronary resistancearteries. Circ Res 93:573–580. doi:10.1161/01.RES.0000091261.19387.AE

    Article  CAS  PubMed  Google Scholar 

  46. Loot AE, Popp R, Fisslthaler B, Vriens J, Nilius B, Fleming I (2008) Role of cytochrome P450-dependent transient receptor potential V4 activation in flow-induced vasodilatation. Cardiovasc Res 80:445–452. doi:10.1093/cvr/cvn207

    Article  CAS  PubMed  Google Scholar 

  47. Ma X, Qiu S, Luo J, Ma Y, Ngai CY, Shen B, Wong CO, Huang Y, Yao X (2010) Functional role of vanilloid transient receptor potential 4-canonical transient receptor potential 1 complex in flow-induced Ca2+ influx. Arterioscler Thromb Vasc Biol 30:851–858. doi:10.1161/ATVBAHA.109.196584

    Article  CAS  PubMed  Google Scholar 

  48. Maiti D, Xu Z, Duh EJ (2008) Vascular endothelial growth factor induces MEF2C and MEF2-dependent activity in endothelial cells. Invest Ophthalmol Vis Sci 49:3640–3648. doi:10.1167/iovs.08-1760

    Article  PubMed Central  PubMed  Google Scholar 

  49. Marrelli SP (2001) Mechanisms of endothelial P2Y(1)- and P2Y(2)-mediated vasodilatation involve differential [Ca2+]i responses. Am J Physiol Heart Circ Physiol 281:H1759–H1766

    CAS  PubMed  Google Scholar 

  50. Martin E, Dahan D, Cardouat G, Gillibert-Duplantier J, Marthan R, Savineau JP, Ducret T (2012) Involvement of TRPV1 and TRPV4 channels in migration of rat pulmonary arterial smooth muscle cells. Pflugers Arch 464:261–272. doi:10.1007/s00424-012-1136-5

    Article  CAS  PubMed  Google Scholar 

  51. Masuyama R, Vriens J, Voets T, Karashima Y, Owsianik G, Vennekens R, Lieben L, Torrekens S, Moermans K, Vanden Bosch A, Bouillon R, Nilius B, Carmeliet G (2008) TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts. Cell Metab 8:257–265. doi:10.1016/j.cmet.2008.08.002

    Article  CAS  PubMed  Google Scholar 

  52. Medvedeva YV, Weiss JH (2014) Intramitochondrial Zn2+ accumulation via the Ca2+ uniporter contributes to acute ischemic neurodegeneration. Neurobiol Dis 68:137–144. doi:10.1016/j.nbd.2014.04.011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Mendoza SA, Fang J, Gutterman DD, Wilcox DA, Bubolz AH, Li R, Suzuki M, Zhang DX (2010) TRPV4-mediated endothelial Ca2+ influx and vasodilation in response to shear stress. Am J Physiol Heart Circ Physiol 298:H466–H476. doi:10.1152/ajpheart.00854.2009

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Miura H, Wachtel RE, Liu Y, Loberiza FR Jr, Saito T, Miura M, Gutterman DD (2001) Flow-induced dilation of human coronary arterioles: important role of Ca(2+)-activated K(+) channels. Circulation 103:1992–1998. doi:10.1161/01.CIR.103.15.1992

    Article  CAS  PubMed  Google Scholar 

  55. Mizuno A, Matsumoto N, Imai M, Suzuki M (2003) Impaired osmotic sensation in mice lacking TRPV4. Am J Physiol Cell Physiol 285:C96–C101. doi:10.1152/ajpcell.00559.2002

    Article  CAS  PubMed  Google Scholar 

  56. Mueller-Tribbensee SM, Karna M, Khalil M, Neurath MF, Reeh PW, Engel MA (2015) Differential contribution of TRPA1, TRPV4 and TRPM8 to colonic nociception in mice. PLoS ONE 10:e0128242. doi:10.1371/journal.pone.0128242

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  57. Muramatsu S, Wakabayashi M, Ohno T, Amano K, Ooishi R, Sugahara T, Shiojiri S, Tashiro K, Suzuki Y, Nishimura R, Kuhara S, Sugano S, Yoneda T, Matsuda A (2007) Functional gene screening system identified TRPV4 as a regulator of chondrogenic differentiation. J Biol Chem 282:32158–32167. doi:10.1074/jbc.M706158200

    Article  CAS  PubMed  Google Scholar 

  58. Nishijima Y, Zheng X, Lund H, Suzuki M, Mattson DL, Zhang DX (2014) Characterization of blood pressure and endothelial function in TRPV4-deficient mice with l-NAME- and angiotensin II-induced hypertension. Physiol Rep 2:e00199. doi:10.1002/phy2.199

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  59. Nozadze I, Tsiklauri N, Gurtskaia G, Tsagareli MG (2015) Role of thermo TRPA1 and TRPV1 channels in heat, cold, and mechanical nociception of rats. Behav Pharmacol

  60. O’Conor CJ, Griffin TM, Liedtke W, Guilak F (2013) Increased susceptibility of Trpv4-deficient mice to obesity and obesity-induced osteoarthritis with very high-fat diet. Ann Rheum Dis 72:300–304. doi:10.1136/annrheumdis-2012-202272

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  61. Okahara K, Sun B, Kambayashi J (1998) Upregulation of prostacyclin synthesis-related gene expression by shear stress in vascular endothelial cells. Arterioscler Thromb Vasc Biol 18:1922–1926. doi:10.1161/01.ATV.18.12.1922

    Article  CAS  PubMed  Google Scholar 

  62. Paniagua OA, Bryant MB, Panza JA (2001) Role of endothelial nitric oxide in shear stress-induced vasodilation of human microvasculature: diminished activity in hypertensive and hypercholesterolemic patients. Circulation 103:1752–175812. doi:10.1161/01.CIR.103.13.1752

    Article  CAS  PubMed  Google Scholar 

  63. Parpaite T, Cardouat G, Mauroux M, Gillibert-Duplantier J, Robillard P, Quignard JF, Marthan R, Savineau JP, Ducret T (2015) Effect of hypoxia on TRPV1 and TRPV4 channels in rat pulmonary arterial smooth muscle cells. Pflugers Arch

  64. Passier R, Zeng H, Frey N, Naya FJ, Nicol RL, McKinsey TA, Overbeek P, Richardson JA, Grant SR, Olson EN (2000) CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo. J Clin Invest 105:1395–1406. doi:10.1172/JCI8551

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Peixoto-Neves D, Wang Q, Leal-Cardoso JH, Rossoni LV, Jaggar JH (2015) Eugenol dilates mesenteric arteries and reduces systemic BP by activating endothelial cell TRPV4 channels. Br J Pharmacol 172:3484–3494. doi:10.1111/bph.13156

    Article  CAS  PubMed  Google Scholar 

  66. Peng TI, Jou MJ (2010) Oxidative stress caused by mitochondrial calcium overload. Ann N Y Acad Sci 1201:183–188. doi:10.1111/j.1749-6632.2010.05634.x

    Article  CAS  PubMed  Google Scholar 

  67. Pokreisz P, Fleming I, Kiss L, Barbosa-Sicard E, Fisslthaler B, Falck JR, Hammock BD, Kim IH, Szelid Z, Vermeersch P, Gillijns H, Pellens M, Grimminger F, van Zonneveld AJ, Collen D, Busse R, Janssens S (2006) Cytochrome P450 epoxygenase gene function in hypoxic pulmonary vasoconstriction and pulmonary vascular remodeling. Hypertension 47:762–770. doi:10.1161/01.HYP.0000208299.62535.58

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Premkumar KV, Chaube SK (2014) RyR channel-mediated increase of cytosolic free calcium level signals cyclin B1 degradation during abortive spontaneous egg activation in rat. In Vitro Cell Dev Biol Anim 50:640–647. doi:10.1007/s11626-014-9749-y

    Article  CAS  PubMed  Google Scholar 

  69. Rahaman SO, Grove LM, Paruchuri S, Southern BD, Abraham S, Niese KA, Scheraga RG, Ghosh S, Thodeti CK, Zhang DX, Moran MM, Schilling WP, Tschumperlin DJ, Olman MA (2014) TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice. J Clin Invest 124:5225–5238. doi:10.1172/JCI75331

    Article  PubMed Central  PubMed  Google Scholar 

  70. Randhawa PK, Jaggi AS (2015) TRPV1 and TRPV4 channels: potential therapeutic targets for ischemic conditioning-induced cardioprotection. Eur J Pharmacol 746:180–185. doi:10.1016/j.ejphar.2014.11.010

    Article  CAS  PubMed  Google Scholar 

  71. Rath G, Saliez J, Behets G, Romero-Perez M, Leon-Gomez E, Bouzin C, Vriens J, Nilius B, Feron O, Dessy C (2012) Vascular hypoxic preconditioning relies on TRPV4 dependent calcium influx and proper intercellular gap junctions communication. Arterioscler ThrombVasc Biol 32:2241–2249. doi:10.1161/ATVBAHA.112.252783

    Article  CAS  Google Scholar 

  72. Robbins N, Koch SE, Rubinstein JF (2013) Targeting TRPV1 and TRPV2 for potential therapeutic interventions in cardiovascular disease. Transl Res 161:469–476. doi:10.1016/j.trsl.2013.02.003

    Article  CAS  PubMed  Google Scholar 

  73. Roderick HL, Cook SJ (2008) Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival. Nat Rev Cancer 8:361–375. doi:10.1038/nrc2374

    Article  CAS  PubMed  Google Scholar 

  74. Saliez J, Bouzin C, Rath G, Ghisdal P, Desjardins F, Rezzani R, Rodella LF, Vriens J, Nilius B, Feron O, Balligand JL, Dessy C (2008) Role of caveolar compartmentation in endothelium-derived hyperpolarizing factor-mediated relaxation: Ca2+ signals and gap junction function are regulated by caveolin in endothelial cells. Circulation 117:1065–1074. doi:10.1161/CIRCULATIONAHA.107.731679

    Article  CAS  PubMed  Google Scholar 

  75. Schulz R, Boengler K, Totzeck A, Luo Y, Garcia-Dorado D, Heusch G (2007) Connexin 43 in ischemic pre- and postconditioning. Heart Fail Rev 12:261–266. doi:10.1007/s10741-007-9032-3

    Article  CAS  PubMed  Google Scholar 

  76. Shiode N, Morishima N, Nakayama K, Yamagata T, Matsuura H, Kajiyama G (1996) Flow-mediated vasodilation of human epicardial coronary arteries: effect of inhibition of nitric oxide synthesis. J Am Coll Cardiol 27:304–310. doi:10.1016/0735-1097(95)00465-3

    Article  CAS  PubMed  Google Scholar 

  77. Sokabe T, Fukumi-Tominaga T, Yonemura S, Mizuno A, Tominaga M (2010) The TRPV4 channel contributes to intercellular junction formation in keratinocytes. J Biol Chem 285:18749–18758. doi:10.1074/jbc.M110.103606

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Song Y, Zhan L, Yu M, Huang C, Meng X, Ma T, Zhang L, Li J (2014) TRPV4 channel inhibits TGF-β1-induced proliferation of hepatic stellate cells. PLoS ONE 9:e101179. doi:10.1371/journal.pone.0101179

    Article  PubMed Central  PubMed  Google Scholar 

  79. Sonkusare SK, Bonev AD, Ledoux J, Liedtke W, Kotlikoff MI, Heppner TJ, Hill-Eubanks DC, Nelson MT (2012) Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function. Science 336:597–601. doi:10.1126/science.1216283

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Sonkusare SK, Dalsgaard T, Bonev AD, Hill-Eubanks DC, Kotlikoff MI, Scott JD, Santana LF, Nelson MT (2014) AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension. Sci Signal 7:66. doi:10.1126/scisignal.2005052

    Article  CAS  Google Scholar 

  81. Sousa-Valente J, Andreou AP, Urban L, Nagy I (2014) Transient receptor potential ion channels in primary sensory neurons as targets for novel analgesics. Br J Pharmacol 171:2508–2527. doi:10.1111/bph.12532

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Strotmann R, Harteneck C, Nunnenmacher K, Schultz G, Plant TD (2000) OTRPC4, a nonselective cation channel that confers sensitivity to extracellular osmolarity. Nat Cell Biol 2:695–702. doi:10.1038/35036318

    Article  CAS  PubMed  Google Scholar 

  83. Sukumaran SV, Singh TU, Parida S, Narasimha Reddy ChE, Thangamalai R, Kandasamy K, Singh V, Mishra SK (2013) TRPV4 channel activation leads to endothelium-dependent relaxation mediated by nitric oxide and endothelium-derived hyperpolarizing factor in rat pulmonary artery. Pharmacol Res 78:18–27. doi:10.1016/j.phrs.2013.09.005

    Article  CAS  PubMed  Google Scholar 

  84. Sun D, Liu H, Yan C, Jacobson A, Ojaimi C, Huang A et al (2006) COX-2 contributes to the maintenance of flow-induced dilation in arterioles of eNOS-knockout mice. Am J Physiol Heart Circ Physiol 291:H1429–H1435. doi:10.1152/ajpheart.01130.2005

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Suzuki M, Mizuno A, Kodaira K, Imai M (2003) Impaired pressure sensation in mice lacking TRPV4. J Biol Chem 278:22664–22668. doi:10.1074/jbc.M302561200

    Article  CAS  PubMed  Google Scholar 

  86. Tabuchi K, Suzuki M, Mizuno A, Hara A (2005) Hearing impairment in TRPV4 knockout mice. Neurosci Lett 382:304–308. doi:10.1016/j.neulet.2005.03.035

    Article  CAS  PubMed  Google Scholar 

  87. Thodeti CK, Matthews B, Ravi A, Mammoto A, Ghosh K, Bracha AL, Ingber DE (2009) TRPV4 channels mediate cyclic strain-induced endothelial cell reorientation through integrin-to-integrin signaling. Circ Res 104:1123–1130. doi:10.1161/CIRCRESAHA.108.192930

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Thorneloe KS, Cheung M, Bao W, Alsaid H, Lenhard S, Jian MY, Costell M, Maniscalco-Hauk K, Krawiec JA, Olzinski A, Gordon E, Lozinskaya I, Elefante L, Qin P, Matasic DS, James C, Tunstead J, Donovan B, Kallal L, Waszkiewicz A, Vaidya K, Davenport EA, Larkin J, Burgert M, Casillas LN, Marquis RW, Ye G, Eidam HS, Goodman KB, Toomey JR, Roethke TJ, Jucker BM, Schnackenberg CG, Townsley MI, Lepore JJ, Willette RN (2012) An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med 4:159ra148. doi:10.1126/scitranslmed.3004276

    Article  PubMed  CAS  Google Scholar 

  89. Traaseth N, Elfering S, Solien J, Haynes V, Giulivi C (2004) Role of calcium signaling in the activation of mitochondrial nitric oxide synthase and citric acid cycle. Biochim Biophys Acta 1658:64–71. doi:10.1016/j.bbabio.2004.04.015

    Article  CAS  PubMed  Google Scholar 

  90. Troidl K, Szardien S, Rolf A, Schmitz-Rixen T, Schaper W, Hamm CW, Elsässer A, Möllmann H (2010) Calcium-dependent signalling is essential during collateral growth in the pig hind limb-ischemia model. J Mol Cell Cardiol 49:142–151. doi:10.1016/j.yjmcc.2010.03.021

    Article  CAS  PubMed  Google Scholar 

  91. Troidl C, Troidl K, Schierling W, Cai WJ, Nef H, Möllmann H, Kostin S, Schimanski S, Hammer L, Elsässer A, Schmitz-Rixen T, Schaper W (2009) Trpv4 induces collateral vessel growth during regeneration of the arterial circulation. J Cell Mol Med 13:2613–2621. doi:10.1111/j.1582-4934.2008.00579.x

    Article  PubMed  Google Scholar 

  92. Vriens J, Owsianik G, Fisslthaler B, Suzuki M, Janssens A, Voets T, Morisseau C, Hammock BD, Fleming I, Busse R, Nilius B (2005) Modulation of the Ca2+ permeable cation channel TRPV4 by cytochrome P450 epoxygenases in vascular endothelium. Circ Res 97:908–915. doi:10.1161/01.RES.0000187474.47805.30

    Article  CAS  PubMed  Google Scholar 

  93. Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nilius B (2003) Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 424:434–438. doi:10.1038/nature01807

    Article  CAS  PubMed  Google Scholar 

  94. Yan H, Hao S, Sun X, Zhang D, Gao X, Yu Z, Li K, Hang CH (2015) Blockage of mitochondrial calcium uniporter prevents iron accumulation in a model of experimental subarachnoid hemorrhage. Biochem Biophys Res Commun 456:835–840. doi:10.1016/j.bbrc.2014.12.073

    Article  CAS  PubMed  Google Scholar 

  95. Yang XR, Lin AH, Hughes JM, Flavahan NA, Cao YN, Liedtke W et al (2012) Upregulation of osmo-mechanosensitive TRPV4 channel facilitates chronic hypoxia-induced myogenic tone and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 302:L555–L568. doi:10.1152/ajplung.00005.2011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Yao X, Garland CJ (2005) Recent developments in vascular endothelial cell transient receptor potential channels. Circ Res 97:853–863. doi:10.1161/01.RES.0000187473.85419.3e

    Article  CAS  PubMed  Google Scholar 

  97. Yoshida T, Inoue R, Morii T, Takahashi N, Yamamoto S, Hara Y, Tominaga M, Shimizu S, Sato Y, Mori Y (2006) Nitric oxide activates TRP channels by cysteine S-nitrosylation. Nat Chem Biol 2:596–607. doi:10.1038/nchembio821

    Article  CAS  PubMed  Google Scholar 

  98. Yu Z, Xu F, Huse LM, Morisseau C, Draper AJ, Newman JW, Parker C, Graham L, Engler MM, Hammock BD, Zeldin DC, Kroetz DL (2000) Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circ Res 87:992–998. doi:10.1161/01.RES.87.11.992

    Article  CAS  PubMed  Google Scholar 

  99. Zaichuk TA, Shroff EH, Emmanuel R, Filleur S, Nelius T, Volpert OV (2004) Nuclear factor of activated T cells balances angiogenesis activation and inhibition. J Exp Med 199:1513–1522. doi:10.1084/jem.20040474

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Zaika O, Mamenko M, Berrout J, Boukelmoune N, O’Neil RG, Pochynyuk O (2013) TRPV4 dysfunction promotes renal cystogenesis in autosomal recessive polycystic kidney disease. J Am Soc Nephrol 24:604–616. doi:10.1681/ASN.2012050442

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  101. Zhang DX, Gutterman DD (2007) Mitochondrial reactive oxygen species-mediated signaling in endothelial cells. Am J Physiol Heart Circ Physiol 292:H2023–H2031. doi:10.1152/ajpheart.01283.2006

    Article  CAS  PubMed  Google Scholar 

  102. Zhang DX, Mendoza SA, Bubolz AH, Mizuno A, Ge ZD, Li R, Warltier DC, Suzuki M, Gutterman DD (2009) Transient receptor potential vanilloid type 4-deficient mice exhibit impaired endothelium-dependent relaxation induced by acetylcholine in vitro and in vivo. Hypertension 53:532–538. doi:10.1161/HYPERTENSIONAHA.108.127100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  103. Zhao L, Sullivan MN, Chase M, Gonzales AL, Earley S (2014) Calcineurin/nuclear factor of activated T cells-coupled vanilliod transient receptor potential channel 4 Ca2+ sparklets stimulate airway smooth muscle cell proliferation. Am J Respir Cell Mol Biol 50:1064–1075. doi:10.1165/rcmb.2013-0416OC

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  104. Zheng X, Zinkevich NS, Gebremedhin D, Gauthier KM, Nishijima Y, Fang J, Wilcox DA, Campbell WB, Gutterman DD, Zhang DX (2013) Arachidonic acid-induced dilation in human coronary arterioles: convergence of signaling mechanisms on endothelial TRPV4-mediated Ca2+ entry. J Am Heart Assoc 2:e000080. doi:10.1161/JAHA.113.000080

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  105. Zheng YM, Wang QS, Rathore R, Zhang WH, Mazurkiewicz JE, Sorrentino V, Singer HA, Kotlikoff MI, Wang YX (2005) Type-3 ryanodine receptors mediate hypoxia-, but not neurotransmitter-induced calcium release and contraction in pulmonary artery smooth muscle cells. J Gen Physiol 125:427–440. doi:10.1085/jgp.200409232

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are thankful to Department of Science and Technology F.No. SB/SO/HS/0004/2013, New Delhi for their gratefulness for providing us financial assistance and Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India for supporting us.

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  1. Department of Pharmaceutical Sciences and Drug Research, Punjabi University Patiala, Patiala, 147002, India

    Puneet Kaur Randhawa & Amteshwar Singh Jaggi

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Randhawa, P.K., Jaggi, A.S. TRPV4 channels: physiological and pathological role in cardiovascular system. Basic Res Cardiol 110, 54 (2015). https://doi.org/10.1007/s00395-015-0512-7

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