Advertisement

Pflügers Archiv - European Journal of Physiology

, Volume 466, Issue 2, pp 237–251 | Cite as

Genetic deletion of aquaporin-1 results in microcardia and low blood pressure in mouse with intact nitric oxide-dependent relaxation, but enhanced prostanoids-dependent relaxation

  • V. Montiel
  • E. Leon Gomez
  • C. Bouzin
  • H. Esfahani
  • M. Romero Perez
  • I. Lobysheva
  • O. Devuyst
  • C. Dessy
  • J. L. Balligand
Integrative physiology

Abstract

The water channels, aquaporins (AQPs) are key mediators of transcellular fluid transport. However, their expression and role in cardiac tissue is poorly characterized. Particularly, AQP1 was suggested to transport other molecules (nitric oxide (NO), hydrogen peroxide (H2O2)) with potential major bearing on cardiovascular physiology. We therefore examined the expression of all AQPs and the phenotype of AQP1 knockout mice (vs. wild-type littermates) under implanted telemetry in vivo, as well as endothelium-dependent relaxation in isolated aortas and resistance vessels ex vivo. Four aquaporins were expressed in wild-type heart tissue (AQP1, AQP7, AQP4, AQP8) and two aquaporins in aortic and mesenteric vessels (AQP1–AQP7). AQP1 was expressed in endothelial as well as cardiac and vascular muscle cells and co-segregated with caveolin-1. AQP1 knockout (KO) mice exhibited a prominent microcardia and decreased myocyte transverse dimensions despite no change in capillary density. Both male and female AQP1 KO mice had lower mean BP, which was not attributable to altered water balance or autonomic dysfunction (from baroreflex and frequency analysis of BP and HR variability). NO-dependent BP variability was unperturbed. Accordingly, endothelium-derived hyperpolarizing factor (EDH(F)) or NO-dependent relaxation were unchanged in aorta or resistance vessels ex vivo. However, AQP1 KO mesenteric vessels exhibited an increase in endothelial prostanoids-dependent relaxation, together with increased expression of COX-2. This enhanced relaxation was abrogated by COX inhibition. We conclude that AQP1 does not regulate the endothelial EDH or NO-dependent relaxation ex vivo or in vivo, but its deletion decreases baseline BP together with increased prostanoids-dependent relaxation in resistance vessels. Strikingly, this was associated with microcardia, unrelated to perturbed angiogenesis. This may raise interest for new inhibitors of AQP1 and their use to treat hypertrophic cardiac remodeling.

Keywords

Aquaporins Blood pressure NO-dependent and independent endothelial function pathway Prostaglandins 

Notes

Acknowledgments

The authors are grateful to Yvette Cnops and Huguette Debaix from the Nephrology laboratory (NEFR/IREC), for their help in the RTqPCR and given some specifics primers for different aquaporins. VM is “Specialist doctorant” of the Fonds National de Recherche Scientifique (FNRS) and was supported by grants from the Fondation Saint Luc and FNRS (to JLB). CD is senior research scientist of the Fonds National de Recherche Scientifique (FNRS). CB is IREC imaging platform coordinator. These studies were supported in part by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant no. 305608 (EURenOmics), the Actions de Recherche Concertées (ARC 10/15-029 and 11/16-039, Communauté Française de Belgique), the FNRS and FRSM, and the Inter-University Attraction Pole (Belgium Federal Government). The Aqp1 mice were initially obtained from A.S. Verkman (University of California, San Francisco, CA).

Ethical standards

The experiments comply with the current laws of Belgium.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Agre P, Lee MD, Devidas S, Guggino WB (1997) Aquaporins and ion conductance. Science 275:1490PubMedCrossRefGoogle Scholar
  2. 2.
    Al Ghouleh I, Frazziano G, Rodriguez AI, Csanyi G, Maniar S, St Croix CM, Kelley EE, Egana LA, Song GJ, Bisello A, Lee YJ, Pagano PJ (2013) Aquaporin 1, Nox1, and Ask1 mediate oxidant-induced smooth muscle cell hypertrophy. Cardiovasc Res 97:134–142PubMedCrossRefGoogle Scholar
  3. 3.
    Beitz E, Wu B, Holm LM, Schultz JE, Zeuthen T (2006) Point mutations in the aromatic/arginine region in aquaporin 1 allow passage of urea, glycerol, ammonia, and protons. Proc Natl Acad Sci U S A 103(2):269–274PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Butler TL, Au CG, Yang B, Egan JR, Tan YM, Hardeman EC, North KN, Verkman AS, Winlaw DS (2006) Cardiac aquaporin expression in humans, rats, and mice. Am J Physiol Heart Circ Physiol 291:H705–H713PubMedCrossRefGoogle Scholar
  5. 5.
    Campbell EM, Birdsell DN, Yool AJ (2012) The activity of human aquaporin 1 as a cGMP-gated cation channel is regulated by tyrosine phosphorylation in the carboxyl-terminal domain. Mol Pharmacol 81:97–105PubMedCrossRefGoogle Scholar
  6. 6.
    Denker BM, Smith BL, Kuhajda FP, Agre P (1988) Identification, purification, and partial characterization of a novel Mr 28,000 integral membrane protein from erythrocytes and renal tubules. J Biol Chem 263:15634–15642PubMedGoogle Scholar
  7. 7.
    Desjardins F, Lobysheva I, Pelat M, Gallez B, Feron O, Dessy C, Balligand JL (2008) Control of blood pressure variability in caveolin-1-deficient mice: role of nitric oxide identified in vivo through spectral analysis. Cardiovasc Res 79:527–536PubMedCrossRefGoogle Scholar
  8. 8.
    Devuyst O, Yool AJ (2010) Aquaporin-1: new developments and perspectives for peritoneal dialysis. Perit Dial Int 30:135–141PubMedCrossRefGoogle Scholar
  9. 9.
    Ding FB, Yan YM, Huang JB, Mei J, Zhu JQ, Liu H (2013) The involvement of AQP1 in heart oedema induced by global myocardial ischemia. Cell Biochem Funct 31:60–64PubMedCrossRefGoogle Scholar
  10. 10.
    Egan JR, Butler TL, Au CG, Tan YM, North KN, Winlaw DS (2006) Myocardial water handling and the role of aquaporins. Biochim Biophys Acta 1758:1043–1052PubMedCrossRefGoogle Scholar
  11. 11.
    Fredenburgh LE, Liang OD, Macias AA, Polte TR, Liu X, Riascos DF, Chung SW, Schissel SL, Ingber DE, Mitsialis SA, Kourembanas S, Perrella MA (2008) Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells. Circulation 117:2114–2122PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Gambert S, Helies-Toussaint C, Grynberg A (2005) Regulation of intermediary metabolism in rat cardiac myocyte by extracellular glycerol. Biochim Biophys Acta 1736:152–162PubMedCrossRefGoogle Scholar
  13. 13.
    Gambert S, Helies-Toussaint C, Grynberg A (2007) Extracellular glycerol regulates the cardiac energy balance in a working rat heart model. Am J Physiol Heart Circ Physiol 292:H1600–H1606PubMedCrossRefGoogle Scholar
  14. 14.
    Garcia F, Kierbel A, Larocca MC, Gradilone SA, Splinter P, LaRusso NF, Marinelli RA (2001) The water channel aquaporin-8 is mainly intracellular in rat hepatocytes, and its plasma membrane insertion is stimulated by cyclic AMP. J Biol Chem 276:12147–12152PubMedCrossRefGoogle Scholar
  15. 15.
    He ZQ, Liang C, Wang H, Wu ZG (2008) Dysfunction of AQP7 in the periadventitial fat: a novel trigger of atherosclerosis. Med Hypotheses 70:92–95PubMedCrossRefGoogle Scholar
  16. 16.
    Hennan JK, Huang J, Barrett TD, Driscoll EM, Willens DE, Park AM, Crofford LJ, Lucchesi BR (2001) Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries. Circulation 104:820–825PubMedCrossRefGoogle Scholar
  17. 17.
    Herrera M, Garvin JL (2007) Novel role of AQP-1 in NO-dependent vasorelaxation. Am J Physiol Ren Physiol 292:F1443–F1451CrossRefGoogle Scholar
  18. 18.
    Herrera M, Garvin JL (2011) Aquaporins as gas channels. Pflugers Arch 462:623–630PubMedCrossRefGoogle Scholar
  19. 19.
    Hibuse T, Maeda N, Nakatsuji H, Tochino Y, Fujita K, Kihara S, Funahashi T, Shimomura I (2009) The heart requires glycerol as an energy substrate through aquaporin 7, a glycerol facilitator. Cardiovasc Res 83:34–41PubMedCrossRefGoogle Scholar
  20. 20.
    Hung KC, Hsieh PM, Hsu CY, Lin CW, Feng GM, Chen YS, Hung CH (2012) Expression of aquaporins in rat liver regeneration. Scand J Gastroenterol 47:676–685PubMedCrossRefGoogle Scholar
  21. 21.
    Ishibashi K, Kondo S, Hara S, Morishita Y (2011) The evolutionary aspects of aquaporin family. Am J Physiol Regul Integr Comp Physiol 300:R566–R576PubMedCrossRefGoogle Scholar
  22. 22.
    Kellen MR, Bassingthwaighte JB (2003) Transient transcapillary exchange of water driven by osmotic forces in the heart. Am J Physiol Heart Circ Physiol 285:H1317–H1331PubMedCentralPubMedGoogle Scholar
  23. 23.
    Leggett K, Maylor J, Undem C, Lai N, Lu W, Schweitzer K, King LS, Myers AC, Sylvester JT, Sidhaye V, Shimoda LA (2012) Hypoxia-induced migration in pulmonary arterial smooth muscle cells requires calcium-dependent upregulation of aquaporin 1. Am J Physiol Lung Cell Mol Physiol 303:L343–L353PubMedCrossRefGoogle Scholar
  24. 24.
    Ma T, Yang B, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS (1998) Severely impaired urinary concentrating ability in transgenic mice lacking aquaporin-1 water channels. J Biol Chem 273:4296–4299PubMedCrossRefGoogle Scholar
  25. 25.
    Ma T, Yang B, Verkman AS (1997) Cloning of a novel water and urea-permeable aquaporin from mouse expressed strongly in colon, placenta, liver, and heart. Biochem Biophys Res Commun 240:324–328PubMedCrossRefGoogle Scholar
  26. 26.
    Maeng M, Olesen PG, Emmertsen NC, Thorwest M, Nielsen TT, Kristensen BO, Falk E, Andersen HR (2001) Time course of vascular remodeling, formation of neointima and formation of neoadventitia after angioplasty in a porcine model. Coron Artery Dis 12:285–293PubMedCrossRefGoogle Scholar
  27. 27.
    Maunsbach AB, Marples D, Chin E, Ning G, Bondy C, Agre P, Nielsen S (1997) Aquaporin-1 water channel expression in human kidney. J Am Soc Nephrol 8:1–14PubMedGoogle Scholar
  28. 28.
    Moniotte S, Belge C, Sekkali B, Massion PB, Rozec B, Dessy C, Balligand JL (2007) Sepsis is associated with an upregulation of functional beta3 adrenoceptors in the myocardium. Eur J Heart Fail 9:1163–1171PubMedCrossRefGoogle Scholar
  29. 29.
    Nagoshi T, Yoshimura M, Rosano GM, Lopaschuk GD, Mochizuki S (2011) Optimization of cardiac metabolism in heart failure. Curr Pharm Des 17:3846–3853PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Ni J, Verbavatz JM, Rippe A, Boisdé I, Moulin P, Rippe B, Verkman AS, Devuyst O (2006) Aquaporin-1 plays an essential role in water permeability and ultrafiltration during peritoneal dialysis. Kidney Int 69:1518–1525PubMedCrossRefGoogle Scholar
  31. 31.
    Ohashi Y, Kawashima S, Hirata K, Yamashita T, Ishida T, Inoue N, Sakoda T, Kurihara H, Yazaki Y, Yokoyama M (1998) Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. J Clin Invest 102:2061–2071PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Page E, Winterfield J, Goings G, Bastawrous A, Upshaw-Earley J (1998) Water channel proteins in rat cardiac myocyte caveolae: osmolarity-dependent reversible internalization. Am J Physiol 274:H1988–H2000PubMedGoogle Scholar
  33. 33.
    Pelat M, Dessy C, Massion P, Desager JP, Feron O, Balligand JL (2003) Rosuvastatin decreases caveolin-1 and improves nitric oxide-dependent heart rate and blood pressure variability in apolipoprotein E−/− mice in vivo. Circulation 107:2480–2486PubMedCrossRefGoogle Scholar
  34. 34.
    Preston GM, Agre P (1991) Isolation of the cDNA for erythrocyte integral membrane protein of 28 kilodaltons: member of an ancient channel family. Proc Natl Acad Sci USA 88:11110–11114PubMedCrossRefGoogle Scholar
  35. 35.
    Rojek A, Praetorius J, Frokiaer J, Nielsen S, Fenton RA (2008) A current view of the mammalian aquaglyceroporins. Annu Rev Physiol 70:301–327PubMedCrossRefGoogle Scholar
  36. 36.
    Rutkovskiy A, Stenslokken KO, Mariero LH, Skrbic B, Amiry-Moghaddam M, Hillestad V, Valen G, Perreault MC, Ottersen OP, Gullestad L, Dahl CP, Vaage J (2012) Aquaporin-4 in the heart: expression, regulation and functional role in ischemia. Basic Res Cardiol 107:280PubMedCrossRefGoogle Scholar
  37. 37.
    Saadoun S, Papadopoulos MC (2010) Aquaporin-4 in brain and spinal cord oedema. Neuroscience 168:1036–1046PubMedCrossRefGoogle Scholar
  38. 38.
    Saadoun S, Papadopoulos MC, Hara-Chikuma M, Verkman AS (2005) Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption. Nature 434:786–792PubMedCrossRefGoogle Scholar
  39. 39.
    Shanahan CM, Connolly DL, Tyson KL, Cary NR, Osbourn JK, Agre P, Weissberg PL (1999) Aquaporin-1 is expressed by vascular smooth muscle cells and mediates rapid water transport across vascular cell membranes. J Vasc Res 36:353–362PubMedCrossRefGoogle Scholar
  40. 40.
    Skowronski MT, Lebeck J, Rojek A, Praetorius J, Fuchtbauer EM, Frokiaer J, Nielsen S (2007) AQP7 is localized in capillaries of adipose tissue, cardiac and striated muscle: implications in glycerol metabolism. Am J Physiol Ren Physiol 292:F956–F965CrossRefGoogle Scholar
  41. 41.
    Tirziu D, Chorianopoulos E, Moodie KL, Palac RT, Zhuang ZW, Tjwa M, Roncal C, Eriksson U, Fu Q, Elfenbein A, Hall AE, Carmeliet P, Moons L, Simons M (2007) Myocardial hypertrophy in the absence of external stimuli is induced by angiogenesis in mice. J Clin Invest 117:3188–3197PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Tradtrantip L, Tajima M, Li L, Verkman AS (2009) Aquaporin water channels in transepithelial fluid transport. J Med Invest 56(Suppl):179–184PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Verkman AS, Yang B (1997) Aquaporins and ion conductance. Science 275:1491PubMedGoogle Scholar
  44. 44.
    Wakayama Y, Inoue M, Kojima H, Jimi T, Shibuya S, Hara H, Oniki H (2004) Expression and localization of aquaporin 7 in normal skeletal myofiber. Cell Tissue Res 316:123–129PubMedCrossRefGoogle Scholar
  45. 45.
    Walsh K, Shiojima I (2007) Cardiac growth and angiogenesis coordinated by intertissue interactions. J Clin Invest 117:3176–3179PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Warth A, Eckle T, Kohler D, Faigle M, Zug S, Klingel K, Eltzschig HK, Wolburg H (2007) Upregulation of the water channel aquaporin-4 as a potential cause of postischemic cell swelling in a murine model of myocardial infarction. Cardiology 107:402–410PubMedCrossRefGoogle Scholar
  47. 47.
    Yan Y, Huang J, Ding F, Mei J, Zhu J, Liu H, Sun K (2013) Aquaporin 1 plays an important role in myocardial edema caused by cardiopulmonary bypass surgery in goat. Int J Mol Med 31:637–643PubMedGoogle Scholar
  48. 48.
    Yool AJ, Brown EA, Flynn GA (2010) Roles for novel pharmacological blockers of aquaporins in the treatment of brain oedema and cancer. Clin Exp Pharmacol Physiol 37:403–409PubMedCrossRefGoogle Scholar
  49. 49.
    Yool AJ, Weinstein AM (2002) New roles for old holes: ion channel function in aquaporin-1. News Physiol Sci 17:68–72PubMedGoogle Scholar
  50. 50.
    Yu J, Yool AJ, Schulten K, Tajkhorshid E (2006) Mechanism of gating and ion conductivity of a possible tetrameric pore in aquaporin-1. Structure 14:1411–1423PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • V. Montiel
    • 1
    • 2
  • E. Leon Gomez
    • 1
  • C. Bouzin
    • 1
  • H. Esfahani
    • 1
  • M. Romero Perez
    • 1
  • I. Lobysheva
    • 1
  • O. Devuyst
    • 2
    • 3
  • C. Dessy
    • 1
  • J. L. Balligand
    • 1
    • 2
  1. 1.Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC)Université catholique de LouvainBrusselsBelgium
  2. 2.Department of MedicineCliniques Universitaires Saint-LucBrusselsBelgium
  3. 3.Pole of Nephrology (NEFR), Institut de Recherche Expérimentale et Clinique (IREC)Université catholique de LouvainBrusselsBelgium

Personalised recommendations