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Neuroscience Bulletin

, Volume 35, Issue 1, pp 67–78 | Cite as

Angiotensin-Converting Enzyme 2 in the Rostral Ventrolateral Medulla Regulates Cholinergic Signaling and Cardiovascular and Sympathetic Responses in Hypertensive Rats

  • Yu Deng
  • Xing Tan
  • Miao-Ling Li
  • Wei-Zhong Wang
  • Yang-Kai WangEmail author
Original Article
  • 56 Downloads

Abstract

The rostral ventrolateral medulla (RVLM) is a key region in cardiovascular regulation. It has been demonstrated that cholinergic synaptic transmission in the RVLM is enhanced in hypertensive rats. Angiotensin-converting enzyme 2 (ACE2) in the brain plays beneficial roles in cardiovascular function in hypertension. The purpose of this study was to determine the effect of ACE2 overexpression in the RVLM on cholinergic synaptic transmission in spontaneously hypertensive rats (SHRs). Four weeks after injecting lentiviral particles containing enhanced green fluorescent protein and ACE2 bilaterally into the RVLM, the blood pressure and heart rate were notably decreased. ACE2 overexpression significantly reduced the concentration of acetylcholine in microdialysis fluid from the RVLM and blunted the decrease in blood pressure evoked by bilateral injection of atropine into the RVLM in SHRs. In conclusion, we suggest that ACE2 overexpression in the RVLM attenuates the enhanced cholinergic synaptic transmission in SHRs.

Keywords

Hypertension Renin-angiotensin system Gene transfer Acetylcholine Sympathetic nerve activity 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81470534, 81770419, 81630012, and 81570385) and the Key Laboratory of Medical Electrophysiology (Southwest Medical University), Ministry of Education of China - No201709 (KeyME-2017-09).

Compliance with Ethical Standards

Conflict of interest

All authors claim that there are no conflict of interest.

References

  1. 1.
    Wang JG, Liu L. Global impact of 2017 American College of Cardiology/American Heart Association Hypertension Guidelines: a perspective from China. Circulation 2018, 137: 546–548.Google Scholar
  2. 2.
    Mankin LA. Update in hypertension therapy. Med Clin North Am 2016, 100: 665–693.Google Scholar
  3. 3.
    Malpas SC. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev 2010, 90: 513–557.Google Scholar
  4. 4.
    Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci 2006, 7: 335–346.Google Scholar
  5. 5.
    Sved AF, Ito S, Sved JC. Brainstem mechanisms of hypertension: role of the rostral ventrolateral medulla. Curr Hypertens Rep 2003, 5: 262–268.Google Scholar
  6. 6.
    Diz DI, Arnold AC, Nautiyal M, Isa K, Shaltout HA, Tallant EA. Angiotensin peptides and central autonomic regulation. Curr Opin Pharmacol 2011, 11: 131–137.Google Scholar
  7. 7.
    Chan SH, Chan JY. Brain stem NOS and ROS in neural mechanisms of hypertension. Antioxid Redox Signal 2014, 20: 146–163.Google Scholar
  8. 8.
    de Wildt DJ, Porsius AJ. Central cardiovascular effects of physostigmine in the cat; possible cholinergic aspects of blood pressure regulation. Arch Int Pharmacodyn Ther 1981, 253: 22–39.Google Scholar
  9. 9.
    Giuliano R, Ruggiero DA, Morrison S, Ernsberger P, Reis DJ. Cholinergic regulation of arterial pressure by the C1 area of the rostral ventrolateral medulla. J Neurosci 1989, 9: 923–942.Google Scholar
  10. 10.
    Brezenoff HE, Giuliano R. Cardiovascular control by cholinergic mechanisms in the central nervous system. Annu Rev Pharmacol Toxicol 1982, 22: 341–381.Google Scholar
  11. 11.
    Kubo T, Fukumori R, Kobayashi M, Yamaguchi H. Altered cholinergic mechanisms and blood pressure regulation in the rostral ventrolateral medulla of DOCA-salt hypertensive rats. Brain Res Bull 1998, 45: 327–332.Google Scholar
  12. 12.
    Kubo T, Ishizuka T, Fukumori R, Asari T, Hagiwara Y. Enhanced release of acetylcholine in the rostral ventrolateral medulla of spontaneously hypertensive rats. Brain Res 1995, 686: 1–9.Google Scholar
  13. 13.
    Lin Q, Li P. Rostral medullary cholinergic mechanisms and chronic stress-induced hypertension. J Auton Nerv Syst 1990, 31: 211–217.Google Scholar
  14. 14.
    Zisman LS, Keller RS, Weaver B, Lin Q, Speth R, Bristow MR, et al. Increased angiotensin-(1–7)-forming activity in failing human heart ventricles: evidence for upregulation of the angiotensin-converting enzyme Homologue ACE2. Circulation 2003, 108: 1707–1712.Google Scholar
  15. 15.
    Der Sarkissian S, Huentelman MJ, Stewart J, Katovich MJ, Raizada MK. ACE2: A novel therapeutic target for cardiovascular diseases. Prog Biophys Mol Biol 2006, 91: 163–198.Google Scholar
  16. 16.
    Feng Y, Xia H, Santos RA, Speth R, Lazartigues E. Angiotensin-converting enzyme 2: a new target for neurogenic hypertension. Exp Physiol 2010, 95: 601–606.Google Scholar
  17. 17.
    de Morais SDB, Shanks J, Zucker IH. Integrative physiological aspects of brain RAS in hypertension. Curr Hypertens Rep 2018, 20: 10.Google Scholar
  18. 18.
    Yamazato M, Yamazato Y, Sun C, Diez-Freire C, Raizada MK. Overexpression of angiotensin-converting enzyme 2 in the rostral ventrolateral medulla causes long-term decrease in blood pressure in the spontaneously hypertensive rats. Hypertension 2007, 49: 926–931.Google Scholar
  19. 19.
    Kubo T, Hagiwara Y, Endo S, Fukumori R. Activation of hypothalamic angiotensin receptors produces pressor responses via cholinergic inputs to the rostral ventrolateral medulla in normotensive and hypertensive rats. Brain Res 2002, 953: 232–245.Google Scholar
  20. 20.
    Agarwal D, Welsch MA, Keller JN, Francis J. Chronic exercise modulates RAS components and improves balance between pro- and anti-inflammatory cytokines in the brain of SHR. Basic Res Cardiol 2011, 106: 1069–1085.Google Scholar
  21. 21.
    Xia H, Suda S, Bindom S, Feng Y, Gurley SB, Seth D, et al. ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. PLoS One 2011, 6: e22682.Google Scholar
  22. 22.
    Tan X, Jiao PL, Wang YK, Wu ZT, Zeng XR, Li ML, et al. The phosphoinositide-3 kinase signaling is involved in neuroinflammation in hypertensive rats. CNS Neurosci Ther 2017, 23: 350–359.Google Scholar
  23. 23.
    Wang YK, Shen D, Hao Q, Yu Q, Wu ZT, Deng Y, et al. Overexpression of angiotensin-converting enzyme 2 attenuates tonically active glutamatergic input to the rostral ventrolateral medulla in hypertensive rats. Am J Physiol Heart Circ Physiol 2014, 307: H182–190.Google Scholar
  24. 24.
    Peng J, Wang YK, Wang LG, Yuan WJ, Su DF, Ni X, et al. Sympathoinhibitory mechanism of moxonidine: role of the inducible nitric oxide synthase in the rostral ventrolateral medulla. Cardiovasc Res 2009, 84: 283–291.Google Scholar
  25. 25.
    Zha YP, Wang YK, Deng Y, Zhang RW, Tan X, Yuan WJ, et al. Exercise training lowers the enhanced tonically active glutamatergic input to the rostral ventrolateral medulla in hypertensive rats. CNS Neurosci Ther 2013, 19: 244–251.Google Scholar
  26. 26.
    Wang W, Zou Z, Tan X, Zhang RW, Ren CZ, Yao XY, et al. Enhancement in tonically active glutamatergic inputs to the rostral ventrolateral medulla contributes to neuropathic pain-induced high blood pressure. Neural Plast 2017, 2017: 4174010.Google Scholar
  27. 27.
    Hao F, Gu Y, Tan X, Deng Y, Wu ZT, Xu MJ, et al. Estrogen replacement reduces oxidative stress in the rostral ventrolateral medulla of ovariectomized rats. Oxid Med Cell Longev 2016, 2016: 2158971.Google Scholar
  28. 28.
    Peng JF, Wu ZT, Wang YK, Yuan WJ, Sun T, Ni X, et al. GABAergic mechanism in the rostral ventrolateral medulla contributes to the hypotension of moxonidine. Cardiovasc Res 2011, 89: 473–481.Google Scholar
  29. 29.
    Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates (3rd ed.). New York: Academic, 1998.Google Scholar
  30. 30.
    Gaede AH, Pilowsky PM. Catestatin in rat RVLM is sympathoexcitatory, increases barosensitivity, and attenuates chemosensitivity and the somatosympathetic reflex. Am J Physiol Regul Integr Comp Physiol 2010, 299: R1538–1545.Google Scholar
  31. 31.
    Madden CJ, Sved AF. Cardiovascular regulation after destruction of the C1 cell group of the rostral ventrolateral medulla in rats. Am J Physiol Heart Circ Physiol 2003, 285: H2734–2748.Google Scholar
  32. 32.
    Milner TA, Hernandez FJ, Herrick SP, Pierce JP, Iadecola C, Drake CT. Cellular and subcellular localization of androgen receptor immunoreactivity relative to C1 adrenergic neurons in the rostral ventrolateral medulla of male and female rats. Synapse 2007, 61: 268–278.Google Scholar
  33. 33.
    Schreihofer AM, Stornetta RL, Guyenet PG. Regulation of sympathetic tone and arterial pressure by rostral ventrolateral medulla after depletion of C1 cells in rat. J Physiol 2000, 529 Pt 1: 221–236.Google Scholar
  34. 34.
    Drolet G, Aslanian V, Minson J, Morris M, Chalmers J. Differences in the central hypotensive actions of alpha-methyldopa and clonidine in the spontaneously hypertensive rat: contribution of neurons arising from the B3 and the C1 areas of the rostral ventrolateral medulla. J Cardiovasc Pharmacol 1990, 15: 118–123.Google Scholar
  35. 35.
    Falquetto B, Tuppy M, Potje SR, Moreira TS, Antoniali C, Takakura AC. Cardiovascular dysfunction associated with neurodegeneration in an experimental model of Parkinson’s disease. Brain Res 2017, 1657: 156–166.Google Scholar
  36. 36.
    Kubo T, Taguchi K, Sawai N, Ozaki S, Hagiwara Y. Cholinergic mechanisms responsible for blood pressure regulation on sympathoexcitatory neurons in the rostral ventrolateral medulla of the rat. Brain Res Bull 1997, 42: 199–204.Google Scholar
  37. 37.
    Samano C, Zetina ME, Cifuentes F, Morales MA. Segregation of met-enkephalin from vesicular acetylcholine transporter and choline acetyltransferase in sympathetic preganglionic varicosities mostly lacking synaptophysin and synaptotagmin. Neuroscience 2009, 163: 180–189.Google Scholar
  38. 38.
    Cham JL, Badoer E. Exposure to a hot environment can activate rostral ventrolateral medulla-projecting neurones in the hypothalamic paraventricular nucleus in conscious rats. Exp Physiol 2008, 93: 64–74.Google Scholar
  39. 39.
    Kubo T, Hagiwara Y, Sekiya D, Chiba S, Fukumori R. Cholinergic inputs to rostral ventrolateral medulla pressor neurons from hypothalamus. Brain Res Bull 2000, 53: 275–282.Google Scholar
  40. 40.
    Stornetta RL, Macon CJ, Nguyen TM, Coates MB, Guyenet PG. Cholinergic neurons in the mouse rostral ventrolateral medulla target sensory afferent areas. Brain Struct Funct 2013, 218: 455–475.Google Scholar
  41. 41.
    Beker F, Weber M, Fink RH, Adams DJ. Muscarinic and nicotinic ACh receptor activation differentially mobilize Ca2+ in rat intracardiac ganglion neurons. J Neurophysiol 2003, 90: 1956–1964.Google Scholar
  42. 42.
    Kumar NN, Ferguson J, Padley JR, Pilowsky PM, Goodchild AK. Differential muscarinic receptor gene expression levels in the ventral medulla of spontaneously hypertensive and Wistar-Kyoto rats: role in sympathetic baroreflex function. J Hypertens 2009, 27: 1001–1008.Google Scholar
  43. 43.
    Padley JR, Kumar NN, Li Q, Nguyen TB, Pilowsky PM, Goodchild AK. Central command regulation of circulatory function mediated by descending pontine cholinergic inputs to sympathoexcitatory rostral ventrolateral medulla neurons. Circ Res 2007, 100: 284–291.Google Scholar
  44. 44.
    Zhou P, Zhu Q, Liu M, Li J, Wang Y, Zhang C, et al. Muscarinic acetylcholine receptor in cerebellar cortex participates in acetylcholine-mediated blood depressor response in rats. Neurosci Lett 2015, 593: 129–133.Google Scholar
  45. 45.
    Ohishi M, Yamamoto K, Rakugi H. Angiotensin (1–7) and other angiotensin peptides. Curr Pharm Des 2013, 19: 3060–3064.Google Scholar
  46. 46.
    Frantz EDC, Giori IG, Machado MV, Magliano DC, Freitas FM, Andrade MSB, et al. High, but not low, exercise volume shifts the balance of renin-angiotensin system toward ACE2/Mas receptor axis in skeletal muscle in obese rats. Am J Physiol Endocrinol Metab 2017, 313: E473–E482.Google Scholar
  47. 47.
    Chang AY, Li FC, Huang CW, Wu JC, Dai KY, Chen CH, et al. Interplay between brain stem angiotensins and monocyte chemoattractant protein-1 as a novel mechanism for pressor response after ischemic stroke. Neurobiol Dis 2014, 71: 292–304.Google Scholar
  48. 48.
    Pandey A, Goru SK, Kadakol A, Malek V, Gaikwad AB. Differential regulation of angiotensin converting enzyme 2 and nuclear factor-kappaB by angiotensin II receptor subtypes in type 2 diabetic kidney. Biochimie 2015, 118: 71–81.Google Scholar
  49. 49.
    Wang X, Ye Y, Gong H, Wu J, Yuan J, Wang S, et al. The effects of different angiotensin II type 1 receptor blockers on the regulation of the ACE-AngII-AT1 and ACE2-Ang(1–7)-Mas axes in pressure overload-induced cardiac remodeling in male mice. J Mol Cell Cardiol 2016, 97: 180–190.Google Scholar
  50. 50.
    Jiang MY, Chen J, Wang J, Xiao F, Zhang HH, Zhang CR, et al. Nitric oxide modulates cardiovascular function in the rat by activating adenosine A2A receptors and inhibiting acetylcholine release in the rostral ventrolateral medulla. Clin Exp Pharmacol Physiol 2011, 38: 380–386.Google Scholar
  51. 51.
    Wu ZT, Ren CZ, Yang YH, Zhang RW, Sun JC, Wang YK, et al. The PI3K signaling-mediated nitric oxide contributes to cardiovascular effects of angiotensin-(1–7) in the nucleus tractus solitarii of rats. Nitric Oxide 2016, 52: 56–65.Google Scholar
  52. 52.
    Feng Y, Xia H, Cai Y, Halabi CM, Becker LK, Santos RA, et al. Brain-selective overexpression of human angiotensin-converting enzyme type 2 attenuates neurogenic hypertension. Circ Res 2010, 106: 373–382.Google Scholar
  53. 53.
    Zheng H, Liu X, Patel KP. Angiotensin-converting enzyme 2 overexpression improves central nitric oxide-mediated sympathetic outflow in chronic heart failure. Am J Physiol Heart Circ Physiol 2011, 301: H2402–2412.Google Scholar
  54. 54.
    de Brito Alves JL, de Oliveira JM, Ferreira DJ, Barros MA, Nogueira VO, Alves DS, et al. Maternal protein restriction induced-hypertension is associated to oxidative disruption at transcriptional and functional levels in the medulla oblongata. Clin Exp Pharmacol Physiol 2016, 43: 1177–1184.Google Scholar
  55. 55.
    Wang L, de Kloet AD, Pati D, Hiller H, Smith JA, Pioquinto DJ, et al. Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors. Neuropharmacology 2016, 105: 114–123.Google Scholar
  56. 56.
    Shi J, Li Q, Wen T. Dendritic cell factor 1-knockout results in visual deficit through the GABA system in mouse primary visual cortex. Neurosci Bull 2018, 34: 465–475.Google Scholar
  57. 57.
    Li Z, You Z, Li M, Pang L, Cheng J, Wang L. Protective effect of resveratrol on the brain in a rat model of epilepsy. Neurosci Bull 2017, 33: 273–280.Google Scholar
  58. 58.
    Cervini R, Berrard S, Bejanin S, Mallet J. Regulation by CDF/LIF and retinoic acid of multiple ChAT mRNAs produced from distinct promoters. Neuroreport 1994, 5: 1346–1348.Google Scholar
  59. 59.
    Kawashima K, Fujii T. Expression of non-neuronal acetylcholine in lymphocytes and its contribution to the regulation of immune function. Front Biosci 2004, 9: 2063–2085.Google Scholar
  60. 60.
    Roh HT, So WY. The effects of aerobic exercise training on oxidant-antioxidant balance, neurotrophic factor levels, and blood-brain barrier function in obese and non-obese men. J Sport Health Sci 2017. 6: 447–453.Google Scholar
  61. 61.
    Roh HT, Cho SY, So WY. Obesity promotes oxidative stress and exacerbates blood-brain barrier disruption after high-intensity exercise. J Sport Health Sci 2017. 6: 225–230.Google Scholar
  62. 62.
    Han Z, Shen F, He Y, Degos V, Camus M, Maze M, et al. Activation of alpha-7 nicotinic acetylcholine receptor reduces ischemic stroke injury through reduction of pro-inflammatory macrophages and oxidative stress. PLoS One 2014, 9: e105711.Google Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Yu Deng
    • 1
    • 3
  • Xing Tan
    • 1
    • 2
  • Miao-Ling Li
    • 4
  • Wei-Zhong Wang
    • 1
    • 2
  • Yang-Kai Wang
    • 1
    • 2
    Email author
  1. 1.Department of PhysiologySecond Military Medical UniversityShanghaiChina
  2. 2.Institution of Polar Medicine Research CenterSecond Military Medical UniversityShanghaiChina
  3. 3.Department of AnesthesiologyChanghai HospitalShanghaiChina
  4. 4.Institute of Cardiovascular Medical ResearchSouthwest Medical UniversityLuzhouChina

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