5-HT promotes pulmonary arterial smooth muscle cell proliferation through the TRPC channel

Han Junli; Tian Hongyan; Liu Ya; Fan Fenling

doi:10.14715/cmb/2018.64.13.17

Issue

Vol. 64 No. 13: Issue 13

Issue Published : November 2, 2018

The undersigned hereby assign all rights, included but not limited to copyright, for this manuscript to CMB Association upon its submission for consideration to publication on Cellular and Molecular Biology. The rights assigned include, but are not limited to, the sole and exclusive rights to license, sell, subsequently assign, derive, distribute, display and reproduce this manuscript, in whole or in part, in any format, electronic or otherwise, including those in existence at the time this agreement was signed. The authors hereby warrant that they have not granted or assigned, and shall not grant or assign, the aforementioned rights to any other person, firm, organization, or other entity. All rights are automatically restored to authors if this manuscript is not accepted for publication.

5-HT promotes pulmonary arterial smooth muscle cell proliferation through the TRPC channel

https://doi.org/10.14715/cmb/2018.64.13.17

Han Junli

Critical Care Medicine Department of Second Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an 710004, China

Tian Hongyan

Peripheral Vascular Department of First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an 710061, China

Liu Ya

Respiration Department of First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an 710061, China

Fan Fenling

Peripheral Vascular Department of First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an 710061, China

Corresponding Author(s) : Tian Hongyan

jp1291@163.com

Cellular and Molecular Biology, Vol. 64 No. 13: Issue 13
Article Published : October 30, 2018

Abstract

Pulmonary arterial hypertension is caused by an imbalance of pulmonary vasoconstriction and vasodilation. Pulmonary arteriolar remodeling is a primary pathological change and proliferation of pulmonary arterial smooth muscle cells (PASMC) is an important pathological basis for pulmonary arteriolar remodeling. Vasoactive substances, such as 5-HT, may play a role in proliferation of PASMC via unknown mechanisms. In vitro experiments with PASMC showed that the TRPC channel inhibitor SKF96365 inhibited the effects 5-HT and DOI on PASMC proliferation and G2M percentage increase, and decreased expression of TRPC1, TRPC6 and calcineurin A/NFATc3 induced by 5-HT and DOI. SKF96365 inhibited binding of NFATc3 and DNA promoted by 5-HT and DOI. Therefore, 5-HT may affect the TRPC channel to promote proliferation of PASMC; upregulate expression of TRPC1, TRPC6, and calcineurin A/NFATc3; and therefore promote NFATc3 nuclear translocation. There may be crosstalk between 5-HT and TRPC, which may contribute to the pathogeneis of pulmonary arterial hypertension and this may be a novel therapeutic target for treating pulmonary arterial hypertension.

Keywords

Pulmonary arterial hypertension 5-HT TRPC channel Cell proliferation NFAT.

Junli, H., Hongyan, T., Ya, L., & Fenling, F. (2018). 5-HT promotes pulmonary arterial smooth muscle cell proliferation through the TRPC channel. Cellular and Molecular Biology, 64(13), 89–96. https://doi.org/10.14715/cmb/2018.64.13.17

Download Citation

References

Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary-hypertension. N Engl J Med 1992; 327: 70-75.
Wharton J, Strange JW, Moller GMO, Growcott EJ, Ren XH, Franklyn AP, et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med 2005; 172: 105-113.
Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: Pulmonary arterial hypertension. Nat Rev Cardiol 2011; 8: 443-455.
Zafrir B, Adir Y, Shehadeh W, Shteinberg M, Salman N, Amir O. The association between obesity, mortality and filling pressures in pulmonary hypertension patients; the "obesity paradox". Respir Med 2013; 107: 139-146.
MacLean MR, Dempsie Y. Serotonin and pulmonary hypertension-from bench to bedside? Curr Opin Pharmacol 2009; 9: 281-286.
Tabima DM, Chesler NC. The effects of vasoactivity and hypoxic pulmonary hypertension on extralobar pulmonary artery biomechanics. J Biomech 2010; 43: 1864-1869.
Tozzi CA, Christiansen DL, Poiani GJ, Riley DJ. Excess collagen in hypertensive pulmonary-arteries decreases vascular distensibility. Am J Respir Crit Care Med 1994; 149: 1317-1326.
McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. Accf/aha 2009 expert consensus document on pulmonary hypertension a report of the american college of cardiology foundation task force on expert consensus documents and the american heart association. J Am Coll Cardiol 2009; 53: 1573-1619.
Guibert C, Ducret T, Savineau J-P. Expression and physiological roles of trp channels in smooth muscle cells transient receptor potential channels. In: Islam MS, ed.: Springer Netherlands; 2011: 687-706.
Tajsic T, Morrell NW. Smooth muscle cell hypertrophy, proliferation, migration and apoptosis in pulmonary hypertension. Comprehensive physiology. John Wiley & Sons, Inc.; 2010.
Dewachter L, Adnot S, Fadel E, Humbert M, Maitre B, Barlier-Mur AM, et al. Angiopoietin/tie2 pathway influences smooth muscle hyperplasia in idiopathic pulmonary hypertension. Am J Respir Crit Care Med 2006; 174: 1025-1033.
Komuro I, Kurihara H, Sugiyama T, Takaku F, Yazaki Y. Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth-muscle cells. FEBS Lett 1988; 238: 249-252.
Morinelli TA, Zhang LM, Newman WH, Meier KE. Thromboxane a(2) prostaglandin h-2-stimulated mitogenesis of coronary-artery smooth-muscle cells involves activation of mitogen-activated protein-kinase and s6 kinase. J Biolo Chem 1994; 269: 5693-5698.
Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: 13-24.
Giaid A, Saleh D. Reduced expression of endothelial nitric-oxide synthase in the lungs of patients with pulmonary-hypertension. N Engl J Med 1995; 333: 214-221.
Yuan SM. Pulmonary artery hypertension: Pertinent vasomotorial cytokines. Eur Cytokine Netw 2017; 28: 1-7.
Ward JPT, Robertson TP, Aaronson PI. Capacitative calcium entry: A central role in hypoxic pulmonary vasoconstriction? Am J Physiol Lung Cell Mol Physiol 2005; 289: 2-4.
Weigand L, Foxson J, Wang J, Shimoda LA, Sylvester JT. Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store-operated ca2+ and nonselective cation channels. Am J Physiol Lung Cell Mol Physiol 2005; 289: 5-13.
Landsberg JW, Yuan JX-J. Calcium and trp channels in pulmonary vascular smooth muscle cell proliferation. Physiol 2004; 19: 44-50.
Ni W, Geddes TJ, Priestley JRC, Szasz T, Kuhn DM, Watts SW. The existence of a local 5-hydroxytryptaminergic system in peripheral arteries. Br J Pharmacol 2008; 154: 663-674.
Jonnakuty C, Gragnoli C. What do we know about serotonin? J Cell Physiol 2008; 217: 301-306.
MacLean MR. Pulmonary hypertension, anorexigens and 5-ht: Pharmacological synergism in action? Trends Pharmacol Sci 1999; 20: 490-495.
Kereveur A, Callebert J, Humbert M, Herve P, Simonneau G, Launay JM, et al. High plasma serotonin levels in primary pulmonary hypertension - effect of long-term epoprostenol (prostacyclin) therapy. Arterioscler Thromb Vasc Biol 2000; 20: 2233-2239.
Eddahibi S, Raffestin B, Pham I, Launay JM, Aegerter P, Sitbon M, et al. Treatment with 5-ht potentiates development of pulmonary hypertension in chronically hypoxic rats. Am J Physiol Heart Circul Physiol 1997; 272: 1173-1181
Dumitrascu R, Kulcke C, Konigshoff M, Kouri F, Yang X, Morrell N, et al. Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats. Eur Resp J 2011; 37: 1104-1118.
Hironaka E, Hongo M, Sakai A, Mawatari E, Terasawa F, Okumura N, et al. Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Cardiovasc Res 2003; 60: 692-699.
Herve P, Launay JM, Scrobohaci ML, Brenot F, Simonneau G, Petitpretz P, et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995; 99: 249-254.
Pakala R, Willerson JT, Benedict CR. Mitogenic effect of serotonin on vascular endothelial cells. Circulation 1994; 90: 1919-1926.
Li MX, Liu Y, Sun XZ, Li ZF, Fang P, He P, et al. Sildenafil inhibits calcineurin/nfatc2-mediated cyclin a expression in pulmonary artery smooth muscle cells. Life Sci 2011; 89: 644-649.
Morecroft I, Pang L, Baranowska M, Nilsen M, Loughlin L, Dempsie Y, et al. In vivo effects of a combined 5-ht(1b) receptor/sert antagonist in experimental pulmonary hypertension. Cardiovasc Res 2010; 85: 593-603.
Zhang B, Liu Y, Luo Y, Niu W, Li ZC. Alteration of serotonin 2c receptor expression in the aorta and the pulmonary artery in rats exposed to hypoxia. Chin J Physiol 2008; 51: 338-347.
Guibert C, Marthan R, Savineau JP. 5-ht induces an arachidonic acid-sensitive calcium influx in rat small intrapulmonary artery. Am J Physiol Lung Cell Mol Physiol 2004; 286: 1228-1236.
Ducret T, Guibert C, Marthan R, Savineau J-P. Serotonin-induced activation of trpv4-like current in rat intrapulmonary arterial smooth muscle cells. Cell Calcium 2008; 43: 315-323.
Ong HL, de Souza LB, Cheng KT, Ambudkar IS. Physiological functions and regulation of trpc channels. Handb Exp Pharmacol 2014; 223: 1005-1034.
Nelson PL, Beck A, Cheng H. Transient receptor proteins illuminated: Current views on trps and disease. Vet J 2011; 187: 153-164.
Yang XR, Lin MJ, Sham JSK. Physiological functions of transient receptor potential channels in pulmonary arterial smooth muscle cells. Adv Exp Med Biol 2010: 109-122.
Ong HL, de Souza LB, Ambudkar IS. Role of trpc channels in store-operated calcium entry. Adv Exp Med Biol 2016; 898: 87-109.
Sweeney M, Yu Y, Platoshyn O, Zhang S, McDaniel SS, Yuan JXJ. Inhibition of endogenous trp1 decreases capacitative ca2+ entry and attenuates pulmonary artery smooth muscle cell proliferation. Am J Physiol Lung Cell Mol Physiol 2002; 283: 144-155.
Weissmann N, Dietrich A, Fuchs B, Kalwa H, Ay M, Dumitrascu R, et al. Classical transient receptor potential channel 6 (trpc6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc Natl Acad Sci U S A 2006; 103: 19093-19098.
Kwan HY, Huang Y, Yao XQ. Regulation of canonical transient receptor potential isoform 3 (trpc3) channel by protein kinase g. Proc Natl Acad Sci U S A 2004; 101: 2625-2630.
Greenwood IA, Ledoux J, Sanguinetti A, Perrino BA, Leblanc N. Calcineurin a alpha but not a beta augments i-cl(ca) in rabbit pulmonary artery smooth muscle cells. J Biol Chem 2004; 279: 38830-38837.
Klee CB, Ren H, Wang X. Regulation of the calmodulin-stimulated protein phosphatase, calcineurin. J Biol Chem 1998; 273: 13367-13370.
Nilsson LM, Nilsson-Ohman J, Zetterqvist AV, Gomez MF. Nuclear factor of activated t-cells transcription factors in the vasculature: The good guys or the bad guys? Curr Opin Lipidology 2008; 19: 483-490.
Ohba T, Watanabe H, Murakami M, Takahashi Y, Iino K, Kuromitsu S, et al. Upregulation of trpc1 in the development of cardiac hypertrophy. J Mol Cell Cardiol 2007; 42: 498-507.
Kuwahara K, Wang Y, McAnally J, Richardson JA, Bassel-Duby R, Hill JA, et al. Trpc6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J Clin Investig 2006; 116: 3114-3126.
Sohn JW, Xu Y, Jones JE, Wickman K, Williams KW, Elmquist JK. Serotonin 2c receptor activates a distinct population of arcuate pro-opiomelanocortin neurons via trpc channels. Neuron 2011; 71: 488-497.
Vindis C, D'Angelo R, Mucher E, Negre-Salvayre A, Parini A, Mialet-Perez J. Essential role of trpc1 channels in cardiomyoblasts hypertrophy mediated by 5-ht(2a) serotonin receptors. Biochem Biophys Res Commun 2010; 391: 979-983.
de Frutos S, Ramiro Diaz JM, Nitta CH, Sherpa ML, Gonzalez Bosc LV. Endothelin-1 contributes to increased nfatc3 activation by chronic hypoxia in pulmonary arteries. Am J Physiol Cell Physiol 2011; 301: 441-450.
Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, et al. The nuclear factor of activated t cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci U S A 2007; 104: 11418-11423.
Hagberg GB, Blomstrand F, Nilsson M, Tamir H, Hansson E. Stimulation of 5-ht2a receptors on astrocytes in primary culture opens voltage-independent ca2+ channels. Neurochem Int 1998; 32: 153-162.

References

Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary-hypertension. N Engl J Med 1992; 327: 70-75.

Wharton J, Strange JW, Moller GMO, Growcott EJ, Ren XH, Franklyn AP, et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med 2005; 172: 105-113.

Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: Pulmonary arterial hypertension. Nat Rev Cardiol 2011; 8: 443-455.

Zafrir B, Adir Y, Shehadeh W, Shteinberg M, Salman N, Amir O. The association between obesity, mortality and filling pressures in pulmonary hypertension patients; the "obesity paradox". Respir Med 2013; 107: 139-146.

MacLean MR, Dempsie Y. Serotonin and pulmonary hypertension-from bench to bedside? Curr Opin Pharmacol 2009; 9: 281-286.

Tabima DM, Chesler NC. The effects of vasoactivity and hypoxic pulmonary hypertension on extralobar pulmonary artery biomechanics. J Biomech 2010; 43: 1864-1869.

Tozzi CA, Christiansen DL, Poiani GJ, Riley DJ. Excess collagen in hypertensive pulmonary-arteries decreases vascular distensibility. Am J Respir Crit Care Med 1994; 149: 1317-1326.

McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. Accf/aha 2009 expert consensus document on pulmonary hypertension a report of the american college of cardiology foundation task force on expert consensus documents and the american heart association. J Am Coll Cardiol 2009; 53: 1573-1619.

Guibert C, Ducret T, Savineau J-P. Expression and physiological roles of trp channels in smooth muscle cells transient receptor potential channels. In: Islam MS, ed.: Springer Netherlands; 2011: 687-706.

Tajsic T, Morrell NW. Smooth muscle cell hypertrophy, proliferation, migration and apoptosis in pulmonary hypertension. Comprehensive physiology. John Wiley & Sons, Inc.; 2010.

Dewachter L, Adnot S, Fadel E, Humbert M, Maitre B, Barlier-Mur AM, et al. Angiopoietin/tie2 pathway influences smooth muscle hyperplasia in idiopathic pulmonary hypertension. Am J Respir Crit Care Med 2006; 174: 1025-1033.

Komuro I, Kurihara H, Sugiyama T, Takaku F, Yazaki Y. Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth-muscle cells. FEBS Lett 1988; 238: 249-252.

Morinelli TA, Zhang LM, Newman WH, Meier KE. Thromboxane a(2) prostaglandin h-2-stimulated mitogenesis of coronary-artery smooth-muscle cells involves activation of mitogen-activated protein-kinase and s6 kinase. J Biolo Chem 1994; 269: 5693-5698.

Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: 13-24.

Giaid A, Saleh D. Reduced expression of endothelial nitric-oxide synthase in the lungs of patients with pulmonary-hypertension. N Engl J Med 1995; 333: 214-221.

Yuan SM. Pulmonary artery hypertension: Pertinent vasomotorial cytokines. Eur Cytokine Netw 2017; 28: 1-7.

Ward JPT, Robertson TP, Aaronson PI. Capacitative calcium entry: A central role in hypoxic pulmonary vasoconstriction? Am J Physiol Lung Cell Mol Physiol 2005; 289: 2-4.

Weigand L, Foxson J, Wang J, Shimoda LA, Sylvester JT. Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store-operated ca2+ and nonselective cation channels. Am J Physiol Lung Cell Mol Physiol 2005; 289: 5-13.

Landsberg JW, Yuan JX-J. Calcium and trp channels in pulmonary vascular smooth muscle cell proliferation. Physiol 2004; 19: 44-50.

Ni W, Geddes TJ, Priestley JRC, Szasz T, Kuhn DM, Watts SW. The existence of a local 5-hydroxytryptaminergic system in peripheral arteries. Br J Pharmacol 2008; 154: 663-674.

Jonnakuty C, Gragnoli C. What do we know about serotonin? J Cell Physiol 2008; 217: 301-306.

MacLean MR. Pulmonary hypertension, anorexigens and 5-ht: Pharmacological synergism in action? Trends Pharmacol Sci 1999; 20: 490-495.

Kereveur A, Callebert J, Humbert M, Herve P, Simonneau G, Launay JM, et al. High plasma serotonin levels in primary pulmonary hypertension - effect of long-term epoprostenol (prostacyclin) therapy. Arterioscler Thromb Vasc Biol 2000; 20: 2233-2239.

Eddahibi S, Raffestin B, Pham I, Launay JM, Aegerter P, Sitbon M, et al. Treatment with 5-ht potentiates development of pulmonary hypertension in chronically hypoxic rats. Am J Physiol Heart Circul Physiol 1997; 272: 1173-1181

Dumitrascu R, Kulcke C, Konigshoff M, Kouri F, Yang X, Morrell N, et al. Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats. Eur Resp J 2011; 37: 1104-1118.

Hironaka E, Hongo M, Sakai A, Mawatari E, Terasawa F, Okumura N, et al. Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats. Cardiovasc Res 2003; 60: 692-699.

Herve P, Launay JM, Scrobohaci ML, Brenot F, Simonneau G, Petitpretz P, et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995; 99: 249-254.

Pakala R, Willerson JT, Benedict CR. Mitogenic effect of serotonin on vascular endothelial cells. Circulation 1994; 90: 1919-1926.

Li MX, Liu Y, Sun XZ, Li ZF, Fang P, He P, et al. Sildenafil inhibits calcineurin/nfatc2-mediated cyclin a expression in pulmonary artery smooth muscle cells. Life Sci 2011; 89: 644-649.

Morecroft I, Pang L, Baranowska M, Nilsen M, Loughlin L, Dempsie Y, et al. In vivo effects of a combined 5-ht(1b) receptor/sert antagonist in experimental pulmonary hypertension. Cardiovasc Res 2010; 85: 593-603.

Zhang B, Liu Y, Luo Y, Niu W, Li ZC. Alteration of serotonin 2c receptor expression in the aorta and the pulmonary artery in rats exposed to hypoxia. Chin J Physiol 2008; 51: 338-347.

Guibert C, Marthan R, Savineau JP. 5-ht induces an arachidonic acid-sensitive calcium influx in rat small intrapulmonary artery. Am J Physiol Lung Cell Mol Physiol 2004; 286: 1228-1236.

Ducret T, Guibert C, Marthan R, Savineau J-P. Serotonin-induced activation of trpv4-like current in rat intrapulmonary arterial smooth muscle cells. Cell Calcium 2008; 43: 315-323.

Ong HL, de Souza LB, Cheng KT, Ambudkar IS. Physiological functions and regulation of trpc channels. Handb Exp Pharmacol 2014; 223: 1005-1034.

Nelson PL, Beck A, Cheng H. Transient receptor proteins illuminated: Current views on trps and disease. Vet J 2011; 187: 153-164.

Yang XR, Lin MJ, Sham JSK. Physiological functions of transient receptor potential channels in pulmonary arterial smooth muscle cells. Adv Exp Med Biol 2010: 109-122.

Ong HL, de Souza LB, Ambudkar IS. Role of trpc channels in store-operated calcium entry. Adv Exp Med Biol 2016; 898: 87-109.

Sweeney M, Yu Y, Platoshyn O, Zhang S, McDaniel SS, Yuan JXJ. Inhibition of endogenous trp1 decreases capacitative ca2+ entry and attenuates pulmonary artery smooth muscle cell proliferation. Am J Physiol Lung Cell Mol Physiol 2002; 283: 144-155.

Weissmann N, Dietrich A, Fuchs B, Kalwa H, Ay M, Dumitrascu R, et al. Classical transient receptor potential channel 6 (trpc6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc Natl Acad Sci U S A 2006; 103: 19093-19098.

Kwan HY, Huang Y, Yao XQ. Regulation of canonical transient receptor potential isoform 3 (trpc3) channel by protein kinase g. Proc Natl Acad Sci U S A 2004; 101: 2625-2630.

Greenwood IA, Ledoux J, Sanguinetti A, Perrino BA, Leblanc N. Calcineurin a alpha but not a beta augments i-cl(ca) in rabbit pulmonary artery smooth muscle cells. J Biol Chem 2004; 279: 38830-38837.

Klee CB, Ren H, Wang X. Regulation of the calmodulin-stimulated protein phosphatase, calcineurin. J Biol Chem 1998; 273: 13367-13370.

Nilsson LM, Nilsson-Ohman J, Zetterqvist AV, Gomez MF. Nuclear factor of activated t-cells transcription factors in the vasculature: The good guys or the bad guys? Curr Opin Lipidology 2008; 19: 483-490.

Ohba T, Watanabe H, Murakami M, Takahashi Y, Iino K, Kuromitsu S, et al. Upregulation of trpc1 in the development of cardiac hypertrophy. J Mol Cell Cardiol 2007; 42: 498-507.

Kuwahara K, Wang Y, McAnally J, Richardson JA, Bassel-Duby R, Hill JA, et al. Trpc6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J Clin Investig 2006; 116: 3114-3126.

Sohn JW, Xu Y, Jones JE, Wickman K, Williams KW, Elmquist JK. Serotonin 2c receptor activates a distinct population of arcuate pro-opiomelanocortin neurons via trpc channels. Neuron 2011; 71: 488-497.

Vindis C, D'Angelo R, Mucher E, Negre-Salvayre A, Parini A, Mialet-Perez J. Essential role of trpc1 channels in cardiomyoblasts hypertrophy mediated by 5-ht(2a) serotonin receptors. Biochem Biophys Res Commun 2010; 391: 979-983.

de Frutos S, Ramiro Diaz JM, Nitta CH, Sherpa ML, Gonzalez Bosc LV. Endothelin-1 contributes to increased nfatc3 activation by chronic hypoxia in pulmonary arteries. Am J Physiol Cell Physiol 2011; 301: 441-450.

Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, et al. The nuclear factor of activated t cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci U S A 2007; 104: 11418-11423.

Hagberg GB, Blomstrand F, Nilsson M, Tamir H, Hansson E. Stimulation of 5-ht2a receptors on astrocytes in primary culture opens voltage-independent ca2+ channels. Neurochem Int 1998; 32: 153-162.

Author biographies is not available.