Skip to main content

Advertisement

Log in

Angiotensin II and Vascular Injury

  • Mediators, Mechanisms, and Pathways in Tissue Injury (T Fujita, Section Editor)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Vascular injury, characterized by endothelial dysfunction, structural remodelling, inflammation and fibrosis, plays an important role in cardiovascular diseases. Cellular processes underlying this include altered vascular smooth muscle cell (VSMC) growth/apoptosis, fibrosis, increased contractility and vascular calcification. Associated with these events is VSMC differentiation and phenotypic switching from a contractile to a proliferative/secretory phenotype. Inflammation, associated with macrophage infiltration and increased expression of redox-sensitive pro-inflammatory genes, also contributes to vascular remodelling. Among the many factors involved in vascular injury is Ang II. Ang II, previously thought to be the sole biologically active downstream peptide of the renin-angiotensin system (RAS), is converted to smaller peptides, [Ang III, Ang IV, Ang-(1-7)], that are functional and that modulate vascular tone and structure. The actions of Ang II are mediated via signalling pathways activated upon binding to AT1R and AT2R. AT1R activation induces effects through PLC-IP3-DAG, MAP kinases, tyrosine kinases, tyrosine phosphatases and RhoA/Rho kinase. Ang II elicits many of its (patho)physiological actions by stimulating reactive oxygen species (ROS) generation through activation of vascular NAD(P)H oxidase (Nox). ROS in turn influence redox-sensitive signalling molecules. Here we discuss the role of Ang II in vascular injury, focusing on molecular mechanisms and cellular processes. Implications in vascular remodelling, inflammation, calcification and atherosclerosis are highlighted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Schiffrin EL, Touyz RM. From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension. Am J Physiol Heart Circ Physiol. 2004;287(2):H435–46.

    CAS  PubMed  Google Scholar 

  2. Touyz RM. The role of angiotensin II in regulating vascular structural and functional changes in hypertension. Curr Hypertens Rep. 2003;5(2):155–64.

    PubMed  Google Scholar 

  3. Aroor AR, Demarco VG, Jia G, Sun Z, Nistala R, Meininger GA, et al. The role of tissue renin-angiotensin-aldosterone system in the development of endothelial dysfunction and arterial stiffness. Front Endocrinol. 2013;4:161–8.

    Google Scholar 

  4. Ferrario CM. New physiological concepts of the renin-angiotensin system from the investigation of precursors and products of angiotensin I metabolism. Hypertension. 2010;55(2):445–52.

    CAS  PubMed  Google Scholar 

  5. Ferrario CM, Ahmad S, Nagata S, Simington SW, Varagic J, Kon N, et al. An evolving story of angiotensin-II-forming pathways in rodents and humans. Clin Sci (Lond). 2014;126(7):461–9.

    CAS  Google Scholar 

  6. Bader M. Tissue renin-angiotensin-aldosterone systems: targets for pharmacological therapy. Annu Rev Pharmacol Toxicol. 2010;50:439–65.

    CAS  PubMed  Google Scholar 

  7. Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med. 1994;330:1431–8.

    CAS  PubMed  Google Scholar 

  8. Intengan HD, Schiffrin EL. Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis. Hypertension. 2001;38:581–7.

    CAS  PubMed  Google Scholar 

  9. Martinez-Lemus LA, Hill MA, Meininger GA. The plastic nature of the vascular wall: a continuum of remodeling events contributing to control of arteriolar diameter and structure. Physiology. 2009;24:45–57.

    PubMed  Google Scholar 

  10. Harrison DG, Vinh A, Lob H, Madhur MS. Role of the adaptive immune system in hypertension. Curr Opin Pharmacol. 2010;10(2):203–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Thatcher S. The adipose renin-angiotensin system: role in cardiovascular disease. Mol Cell Endocrinol. 2009;302(2):111–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med. 2007;204(10):2449–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Prieto MC, Gonzalez AA, Navar LG. Evolving concepts on regulation and function of renin in distal nephron. Pflugers Arch. 2013;465(1):121–32.

    CAS  PubMed  Google Scholar 

  14. Cassis LA. Local adipose tissue renin-angiotensin system. Curr Hypertens Rep. 2008;10(2):93–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Miyazaki M, Takai S. Tissue angiotensin II generating system by angiotensin-converting enzyme and chymase. J Pharmacol Sci. 2006;100(5):391–7.

    CAS  PubMed  Google Scholar 

  16. Reudelhuber TL. Prorenin, Renin, and their receptor: moving targets. Hypertension. 2010;55(5):1071–107.

    CAS  PubMed  Google Scholar 

  17. Danser AJ, Nguyen G. The Renin Academy Summit: advancing the understanding of renin science. J Renin-Angiotensin-Aldosterone Syst. 2008;9(2):119–23.

    CAS  PubMed  Google Scholar 

  18. Nguyen G, Muller DN. The biology of the (pro)renin receptor. J Am Soc Nephrol. 2010;21(1):8–23.

    Google Scholar 

  19. Nguyen G. The (pro)renin receptor in health and disease. Ann Med. 2010;42(1):13–8.

    CAS  PubMed  Google Scholar 

  20. Hitom H, Liu G, Nishiyama A. Role of (pro)renin receptor in cardiovascular cells from the aspect of signaling. Front Biosci. 2010;2:1246–9.

    Google Scholar 

  21. Advani A, Kelly DJ, Cox AJ, White KE, Advani SL, Thai K, et al. The (pro)renin receptor: site-specific and functional linkage to the vacuolar H+ -ATPase in the kidney. Hypertension. 2009;54:261–9.

    CAS  PubMed  Google Scholar 

  22. Cousin C, Bracquart D, Contrepas A, Nguyen G. Potential role of the (pro)renin receptor in cardiovascular and kidney diseases. J Nephrol. 2010;23:508–13.

    PubMed  Google Scholar 

  23. Xia H, Lazartigues E. Angiotensin-converting enzyme 2: central regulator for cardiovascular function. Curr Hypertens Rep. 2010;12(3):170–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bader M. ACE2, angiotensin-(1–7), and Mas: the other side of the coin. Pflugers Arch. 2013;465(1):79–85.

    CAS  PubMed  Google Scholar 

  25. Shaltout HA. Alterations in circulatory and renal angiotensin-converting enzyme and angiotensin-converting enzyme 2 in fetal programmed hypertension. Hypertension. 2009;53(2):404–8.

    CAS  PubMed  Google Scholar 

  26. Fraga-Silva RA, Savergnini SQ, Montecucco F, Nencioni A, Caffa I, Soncini D, et al. Treatment with Angiotensin-(1-7) reduces inflammation in carotid atherosclerotic plaques. Thromb Haemost. 2014;111(4):736–47.

    CAS  PubMed  Google Scholar 

  27. Imai Y. Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis. Circ J. 2010;74(3):405–10.

    CAS  PubMed  Google Scholar 

  28. Ferrario CM, Iyer SN. Angiotensin-(1-7): a bioactive fragment of the renin-angiotensin system. Regul Pept. 1998;78(1–3):13–8.

    CAS  PubMed  Google Scholar 

  29. Santiago NM. Lifetime overproduction of circulating Angiotensin-(1-7) attenuates deoxycorticosterone acetate-salt hypertension-induced cardiac dysfunction and remodeling. Hypertension. 2010;55(4):889–96.

    CAS  PubMed  Google Scholar 

  30. Cangussu LM. Angiotensin-(1-7) antagonist, A-779, microinjection into the caudal ventrolateral medulla of renovascular hypertensive rats restores baroreflex bradycardia. Peptides. 2009;30(10):1921–7.

    CAS  PubMed  Google Scholar 

  31. Silva DM. Evidence for a new angiotensin-(1-7) receptor subtype in the aorta of Sprague-Dawley rats. Peptides. 2007;28(3):702–7.

    CAS  PubMed  Google Scholar 

  32. Santos RA, Ferreira AJ, Simões E, Silva AC. Recent advances in the angiotensin-converting enzyme 2-angiotensin(1-7)-Mas axis. Exp Physiol. 2008;93(5):519–27.

    CAS  PubMed  Google Scholar 

  33. Sampaio WO, Souza dos Santos RA, Faria-Silva R, da Mata Machado LT, Schiffrin EL, Touyz RM. Angiotensin-(1-7) counter-regulates angiotensin II signaling in human endothelial cells. Hypertension. 2007;50(6):1093–8.

    CAS  PubMed  Google Scholar 

  34. Gwathmey TM, Pendergrass KD, Reid SD, Rose JC, Diz DI, Chappell MC. Angiotensin-(1-7)-angiotensin-converting enzyme 2 attenuates reactive oxygen species formation to angiotensin II within the cell nucleus. Hypertension. 2010;55(1):66–171.

    Google Scholar 

  35. Santos RA, Frézard F, Ferreira AJ. Angiotensin-(1-7): blood, heart, and blood vessels. Curr Med Chem Cardiovasc Hematol Agents. 2005;3(4):383–91.

    CAS  PubMed  Google Scholar 

  36. Reaux A, Fournie-Zaluski MC, Llorens-Cortes C. Angiotensin III: a central regulator of vasopressin release and blood pressure. Trends Endocrinol Metab. 2001;12(4):157–62.

    CAS  PubMed  Google Scholar 

  37. Yang R, Walther T, Gembardt F, Smolders I, Vanderheyden P, Albiston AL, et al. Renal vasoconstrictor and pressor responses to angiotensin IV in mice are AT1a-receptor mediated. J Hypertens. 2010;28(3):487–94.

    CAS  PubMed  Google Scholar 

  38. Ferreira PM, Souza Dos Santos RA, Campagnole-Santos MJ. Angiotensin-(3-7) pressor effect at the rostral ventrolateral medulla. Regul Pept. 2007;141(1–3):168–74.

    CAS  PubMed  Google Scholar 

  39. Ocaranza MP, Jalil JE. Protective role of the ACE2/Ang-(1-9) axis in cardiovascular remodeling. Int J Hypertens. 2012;2012:594–361.

    Google Scholar 

  40. Ahmad S, Wei CC, Tallaj J, Dell'Italia LJ, Moniwa N, Varagic J, et al. Chymase mediates angiotensin-(1-12) metabolism in normal human hearts. J Am Soc Hypertens. 2013;7(2):128–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Vaajanen A, Luhtala S, Oksala O, Vapaatalo H. Does the renin-angiotensin system also regulate intra-ocular pressure? Ann Med. 2008;40(6):418–27.

    CAS  PubMed  Google Scholar 

  42. Wilkinson-Berka JL, Agrotis A, Deliyanti D. The retinal renin-angiotensin system: roles of angiotensin II and aldosterone. Peptides. 2012;36(1):142–50.

    CAS  PubMed  Google Scholar 

  43. Kumar R, Singh VP, Baker KM. The intracellular renin-angiotensin system in the heart. Curr Hypertens Rep. 2009;11(2):104–10.

    CAS  PubMed  Google Scholar 

  44. deGasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International union of pharmacology XXII. The angiotension II receptors. Pharmacol Rev. 2000;52:415–72.

    CAS  Google Scholar 

  45. Namsolleck P, Recarti C, Foulquier S, Steckelings UM, Unger T. AT(2) receptor and tissue injury: therapeutic implications. Curr Hypertens Rep. 2014;16(2):416.

    PubMed  PubMed Central  Google Scholar 

  46. Carey RM, Padia SH. Role of angiotensin AT(2) receptors in natriuresis: Intrarenal mechanisms and therapeutic potential. Clin Exp Pharmacol Physiol. 2013;40(8):527–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Levy BI. How to explain the differences between renin-angiotensin system modulators. Am J Hypertens. 2005;18:134S–41S.

    CAS  PubMed  Google Scholar 

  48. Higuchi S, Ohtsu H, Suzuki H, Shirai H, Frank GD, Eguchi S. Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. Clin Sci (Lond). 2007;112(8):417–28.

    CAS  Google Scholar 

  49. Matsubara H. Pathophysiological role of angiotensin II type 2 receptor in cardiovascular and renal disease. Circ Res. 1998;83:1182–91.

    CAS  PubMed  Google Scholar 

  50. Steckelings UM, Kaschina E, Unger. The AT2 receptor—A matter of love or hate. Peptides. 2005;26:1401–9.

    CAS  PubMed  Google Scholar 

  51. Tamura K, Wakui H, Maeda A, Dejima T, Ohsawa M, Azushima K, et al. The physiology and pathophysiology of a novel angiotensin receptor-binding protein ATRAP/Agtrap. Curr Pharm Des. 2013;19(17):3043–8.

    CAS  PubMed  Google Scholar 

  52. Wakui H, Dejima T, Tamura K, Uneda K, Azuma K, Maeda A, et al. Activation of angiotensin II type 1 receptor-associated protein exerts an inhibitory effect on vascular hypertrophy and oxidative stress in angiotensin II-mediated hypertension. Cardiovasc Res. 2013;100(3):511–9.

    CAS  PubMed  Google Scholar 

  53. Oppermann M, Gess B, Schweda F, Castrop H. Atrap deficiency increases arterial blood pressure and plasma volume. J Am Soc Nephrol. 2010;21(3):468–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Mogi M, Iwai M, Horiuchi M. Emerging concepts of regulation of angiotensin II receptors: new players and targets for traditional receptors. Arterioscler Thromb Vasc Biol. 2007;27(12):2532–9.

    CAS  PubMed  Google Scholar 

  55. Nouet S, Amzallag N. Trans-inactivation of receptor tyrosine kinases by novel angiotensin II AT2 receptor-interacting protein, ATIP. J Biol Chem. 2004;279:28989–97.

    CAS  PubMed  Google Scholar 

  56. Di Benedetto M. Structural organization and expression of human MTUS1, a candidate 8p22 tumor suppressor gene encoding a family of angiotensin II AT2 receptor-interacting proteins, ATIP. Gene. 2006;380(2):127–36.

    PubMed  Google Scholar 

  57. Henrion D, Kubis N, Lévy BI. Physiological and pathophysiological functions of the AT2 subtype receptor of angiotensin II - From large arteries to the microcirculation. Hypertension. 2001;38:1150–7.

    CAS  PubMed  Google Scholar 

  58. Akishita M. Inflammation influences vascular remodeling through AT2 receptor expression and signaling. Physiol Genomics. 2000;2:13–20.

    CAS  PubMed  Google Scholar 

  59. Touyz RM, He G, Deng LY, Schiffrin EL. Role of extracellular signal-regulated kinases in angiotensin II-Stimulated contraction of smooth muscle cells from human resistance arteries. Circulation. 1999;99:392–9.

    CAS  PubMed  Google Scholar 

  60. Xi XP. Central role of the MAPK pathway in Ang II-mediated DNA synthesis and migration in rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1999;19:73–82.

    CAS  PubMed  Google Scholar 

  61. Eguchi S, Inagami T. Signal transduction of angiotensin II type 1 receptor through receptor tyrosine kinase. Regul Pept. 2000;91:13–20.

    CAS  PubMed  Google Scholar 

  62. Montezano AC, Callera GE, Yogi A, He Y, Tostes RC, He G, et al. Aldosterone and angiotensin II synergistically stimulate migration in vascular smooth muscle cells through c-Src-regulated redox-sensitive RhoA pathways. Arterioscler Thromb Vasc Biol. 2008;28(8):1511–8.

    CAS  PubMed  Google Scholar 

  63. Touyz RM, Schiffrin EL. Role of calcium influx and intracellular calcium stores in angiotensin II-mediated calcium hyper-responsiveness in smooth muscle from spontaneously hypertensive rats. J Hypertens. 1997;15:1431–9.

    CAS  PubMed  Google Scholar 

  64. Touyz RM, Yao G, Schiffrin EL. c-Src induces phosphorylation and translocation of p47phox - Role in superoxide generation by angiotensin II in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2003;23:981–7.

    CAS  PubMed  Google Scholar 

  65. Callera GE, Yogi A, Briones AM, Montezano AC, He Y, Tostes RC, et al. Vascular proinflammatory responses by aldosterone are mediated via c-Src trafficking to cholesterol-rich microdomains: role of PDGFR. Cardiovasc Res. 2011;91(4):720–31.

    CAS  PubMed  Google Scholar 

  66. Touyz RM. Increased angiotensin II-mediated Src signaling via epidermal growth factor receptor transactivation is associated with decreased c-terminal Src kinase activity in vascular smooth muscle cells from spontaneously hypertensive rats. Hypertension. 2002;39:479–85.

    CAS  PubMed  Google Scholar 

  67. Touyz RM. Src is an important mediator of extracellular signal-regulated kinase 1/2-dependent growth signaling by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients. Hypertension. 2001;38:56–64.

    CAS  PubMed  Google Scholar 

  68. Saito Y, Berk BC. Transactivation: a novel signaling pathway from angiotensin II to tyrosine kinase receptors. J Mol Cell Cardiol. 2001;33:3–7.

    CAS  PubMed  Google Scholar 

  69. Burger D, Montezano AC, Nishigaki N, He Y, Carter A, Touyz RM. Endothelial microparticle formation by angiotensin II is mediated via Ang II receptor type I/NADPH oxidase/ Rho kinase pathways targeted to lipid rafts. Arterioscler Thromb Vasc Biol. 2011;31(8):1898–907.

    CAS  PubMed  Google Scholar 

  70. Ohtsu H, Dempsey PJ, Frank GD, Brailoiu E, Higuchi S, Suzuki H, et al. ADAM17 mediates epidermal growth factor receptor transactivation and vascular smooth muscle cell hypertrophy induced by angiotensin II. Arterioscler Thromb Vasc Biol. 2006;26(9):e133–7.

    PubMed  Google Scholar 

  71. Loirand G, Pacaud P. The role of Rho protein signaling in hypertension. Nat Rev Cardiol. 2010;7(11):637–47.

    CAS  PubMed  Google Scholar 

  72. Uehata M, Ishizaki T, Satoh H. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997;389(6654):990–4.

    CAS  PubMed  Google Scholar 

  73. Guilluy C, Bregeon J, Tourmaniantz G. The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure. Nat Med. 2010;16:183–90.

    CAS  PubMed  Google Scholar 

  74. Bregeon J, Loirand G, Pacaud P. Angiotensin II induces RhoA activation through SHP2-dependent dephosphorylation of the RhoGAP p190A in vascular smooth muscle cells. Am J Physiol Cell Physiol. 2009;297(5):C1062–70.

    CAS  PubMed  Google Scholar 

  75. Cario-Toumaniantz C, Ferland-McCollough D, Chadeuf G, Toumaniantz G, Rodriguez M, Galizzi JP, et al. RhoA guanine exchange factor expression profile in arteries: evidence for a Rho kinase-dependent negative feedback in angiotensin II-dependent hypertension. Am J Physiol Cell Physiol. 2012;302:C1394–404.

    CAS  PubMed  Google Scholar 

  76. Kobayashi N, Nakano S, Mita S, Kobayashi T, Honda T, Tsubokou Y, et al. Involvement of Rho-kinase pathway for angiotensin II-induced plasminogen activator inhibitor-1 gene expression and cardiovascular remodeling in hypertensive rats. J Pharmacol Exp Ther. 2002;301:459–66.

    CAS  PubMed  Google Scholar 

  77. Touyz RM. Reactive oxygen species and angiotensin II signaling in vascular cells – implications in cardiovascular disease. Braz J Med Biol Res. 2004;37(8):1263–73.

    CAS  PubMed  Google Scholar 

  78. Taniyama Y, Griendling KK. Reactive oxygen species in the vasculature: molecular and cellular mechanisms. Hypertension. 2003;42:1075–81.

    CAS  PubMed  Google Scholar 

  79. Touyz RM, Briones AM, Sedeek M, Burger D, Montezano AC. NOX isoforms and reactive oxygen species in vascular health. Mol Interv. 2011;11(1):27–35.

    CAS  PubMed  Google Scholar 

  80. Lassegue B, Clempus RE. Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol. 2003;285(2):R277–97.

    CAS  PubMed  Google Scholar 

  81. Rey FE, Pagano PJ. The reactive adventitia: fibroblast oxidase in vascular function. Arterioscler Thromb Vasc Biol. 2002;22(12):1962–71.

    CAS  PubMed  Google Scholar 

  82. Montezano AC, Touyz RM. Molecular mechanisms of hypertension–reactive oxygen species and antioxidants: a basic science update for the clinician. Can J Cardiol. 2012;28(3):288–95.

    CAS  PubMed  Google Scholar 

  83. Griendling KK. Novel NAD(P)H oxidases in the cardiovascular system. Heart. 2004;90(5):491–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Briones AM, Touyz RM. Oxidative stress and hypertension: current concepts. Curr Hypertens Rep. 2010;12(2):135–42.

    CAS  PubMed  Google Scholar 

  85. Gray SP, Di Marco E, Okabe J, Szyndralewiez C, Heitz F, Montezano AC, et al. NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis. Circulation. 2013;127(18):1888–902.

    CAS  PubMed  Google Scholar 

  86. Nguyen Dinh Cat A, Montezano AC, Burger D, Touyz RM. Angiotensin II, NADPH oxidase, and redox signaling in the vasculature. Antioxid Redox Signal. 2013;19(10):1110–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Schramm A, Matusik P, Osmenda G, Guzik TJ. Targeting NADPH oxidases in vascular pharmacology. Vasc Pharmacol. 2012;56(5–6):216–31.

    CAS  Google Scholar 

  88. Montezano AC, Burger D, Paravicini TM, Chignalia AZ, Yusuf H, Almasri M, et al. Nicotinamide adenine dinucleotide phosphate reduced oxidase 5 (Nox5) regulation by angiotensin II and endothelin-1 is mediated via calcium/calmodulin-dependent, rac-1-independent pathways in human endothelial cells. Circ Res. 2010;106(8):1363–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Holterman CE, Thibodeau JF, Towaij C, Gutsol A, Montezano AC, Parks RJ, et al. Nephropathy and elevated bp in mice with podocyte-specific NADPH oxidase 5 expression. J Am Soc Nephrol. 2013;25:784–97.

    PubMed  PubMed Central  Google Scholar 

  90. Montezano AC, Touyz RM. Reactive oxygen species, vascular Noxs, and hypertension: focus on translational and clinical research. Antioxid Redox Signal. 2014;20(1):164–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Touyz RM, Chen X, Tabet F, Yao G, He G, Quinn MT, et al. Expression of a gp91phox-containing leukocyte-type NADPH oxidase in human vascular smooth muscle cells—modulation by Ang II. Circ Res. 2006;90:1205–13.

    Google Scholar 

  92. Paravicini TM, Montezano AC, Yusuf H. Touyz RM activation of vascular p38MAPK by mechanical stretch is independent of c-Src and NADPH oxidase: influence of hypertension and angiotensin II. J Am Soc Hypertens. 2012;6(3):169–78. This study clearly identifies differential mechanisms whereby Ang II and blood pressure influence mechanosensitive signaling in vascular smooth muscle cells.

    CAS  PubMed  Google Scholar 

  93. Touyz RM, Schiffrin EL. Ang II-stimulated superoxide production is mediated via phospholipase D in human vascular smooth muscle cells. Hypertension. 1999;34(4):976–82.

    CAS  PubMed  Google Scholar 

  94. Touyz RM, Schiffrin EL. Increased generation of superoxide by angiotensin II in smooth muscle cells from resistance arteries of hypertensive patients: role of phospholipase D-dependent NAD(P)H oxidase-sensitive pathways. J Hypertens. 2001;19:1245–54.

    CAS  PubMed  Google Scholar 

  95. Touyz RM. Oxidative stress and vascular damage in hypertension. Curr Hypertens Rep. 2001;2:98–105.

    Google Scholar 

  96. Petrovič D. Association of the -262C/T polymorphism in the catalase gene promoter and the C242T polymorphism of the NADPH oxidase P22phox gene with essential arterial hypertension in patients with diabetes mellitus type 2. Clin Exp Hypertens. 2014;36(1):36–40.

    PubMed  Google Scholar 

  97. Virdis A, Neves MF, Amiri F, Touyz RM, Schiffrin EL. Role of NAD(P)H oxidase on vascular alterations in angiotensin II-infused mice. J Hypertens. 2004;22(3):535–42.

    CAS  PubMed  Google Scholar 

  98. Chiarugi P, Cirri P. Redox regulation of protein tyrosine phosphatases during receptor tyrosine kinase signal transduction. Trends Biochem Sci. 2003;28:509–14.

    CAS  PubMed  Google Scholar 

  99. Nathan C. Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling. J Clin Invest. 2003;111:769–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Torres M, Forman HJ. Redox signaling and the MAP kinase pathways. Biofactors. 2003;17:287–96.

    CAS  PubMed  Google Scholar 

  101. Tabet F, Schiffrin EL, Callera GE, He Y, Yao G, Ostman A, et al. Redox-sensitive signaling by angiotensin II involves oxidative inactivation and blunted phosphorylation of protein tyrosine phosphatase SHP-2 in vascular smooth muscle cells from SHR. Circ Res. 2008;103(2):149–58.

    CAS  PubMed  Google Scholar 

  102. Sedeek M, Gutsol A, Montezano AC, Burger D, Nguyen Dinh Cat A, Kennedy CR, et al. Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes. Clin Sci (Lond). 2013;124(3):191–202. An in vivo study demonstrating that an orally active inhibitor of Nox1 and Nox4 ameliorates development of nephropathy in a model of diabetes, indicating a role for Nox1/4-derived reactive oxygen in diabetic nephropathy.

    CAS  Google Scholar 

  103. Dohi Y. Candesartan reduces oxidative stress and inflammation in patients with essential hypertension. Hypertens Res. 2003;26:691–7.

    CAS  PubMed  Google Scholar 

  104. Kamiyama M, Urushihara M, Morikawa T, Konishi Y, Imanishi M, Nishiyama A, et al. Oxidative stress/angiotensinogen/renin-angiotensin system axis in patients with diabetic nephropathy. Int J Mol Sci. 2013;14(11):23045–62.

    PubMed  PubMed Central  Google Scholar 

  105. Lacolley P, Regnault V, Nicoletti A, Li Z, Michel JB. The vascular smooth muscle cell in arterial pathology: a cell that can take on multiple roles. Cardiovasc Res. 2012;95(2):194–204.

    CAS  PubMed  Google Scholar 

  106. Savoia C, Burger D, Nishigaki N, Montezano A, Touyz RM. Angiotensin II and the vascular phenotype in hypertension. Expert Rev Mol Med. 2011;13:e11.

    PubMed  Google Scholar 

  107. Albinsson S, Sessa WC. Can microRNAs control vascular smooth muscle phenotypic modulation and the response to injury? Physiol Genomics. 2011;43(10):529–33.

    CAS  PubMed  Google Scholar 

  108. Tayebjee MH, MacFadyen RJ, Lip GY. Extracellular matrix biology: a new frontier in linking the pathology and therapy of hypertension? J Hypertens. 2003;21:2211–8.

    CAS  PubMed  Google Scholar 

  109. Delva P. Collagen I, and III mRNA gene expression and cell growth potential of skin fibroblasts in patients with essential hypertension. J Hypertens. 2002;20:1393–9.

    CAS  PubMed  Google Scholar 

  110. Castro MM, Rizzi E, Prado CM, Rossi MA, Tanus-Santos JE, Gerlach RF. Imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases in hypertensive vascular remodeling. Matrix Biol. 2010;29(3):194–201.

    CAS  PubMed  Google Scholar 

  111. Satoh C. Role of endogenous angiotensin II in the increased expression of growth factors in vascular smooth muscle cells from spontaneously hypertensive rats. J Cardiovasc Pharmacol. 2001;37(1):108–18.

    CAS  PubMed  Google Scholar 

  112. Bobik A. Hypertension, transforming growth factor-β, angiotensin II and kidney disease. J Hypertens. 2004;22(7):1265–7.

    CAS  PubMed  Google Scholar 

  113. Bruder-Nascimento T, Chinnasamy P, Riascos-Bernal DF, Cau SB, Callera GE, Touyz RM, et al. Angiotensin II induces Fat1 expression/activation and vascular smooth muscle cell migration via Nox1-dependent reactive oxygen species generation. J Mol Cell Cardiol. 2014;66:18–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Viel EC, Lemarié CA, Benkirane K, Paradis P, Schiffrin EL. Immune regulation and vascular inflammation in genetic hypertension. Am J Physiol Heart Circ Physiol. 2010;298(3):H938–44.

    CAS  PubMed  Google Scholar 

  115. Zhao Q, Ishibashi M, Hiasa K, Tan C, Takeshita A, Egashira K. Essential role of vascular endothelial growth factor in angiotensin II-induced vascular inflammation and remodeling. Hypertension. 2004;44(3):264–70.

    CAS  PubMed  Google Scholar 

  116. Kasal DA, Barhoumi T, Li MW, Yamamoto N, Zdanovich E, Rehman A, et al. T Regulatory Lymphocytes Prevent Aldosterone-Induced Vascular Injury. Hypertension. 2012;59:324–30. An elegant study showing that adoptive transfer of T regulatory lymphocytes ameliorates vascular injury in mice infused with aldosterone, supporting a role for innate and adaptive immunity in vascular damage associated with activation of the renin angiotensin aldosterone system.

    CAS  PubMed  Google Scholar 

  117. Marvar PJ, Thabet SR, Guzik TJ, Lob HE, McCann LA, Weyand C, et al. Central and peripheral mechanisms of T-lymphocyte activation and vascular inflammation produced by angiotensin II-induced hypertension. Circ Res. 2010;107(2):263–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Hoch NE, Guzik TJ, Chen W, Deans T, Maalouf SA, Gratze P, et al. Regulation of T-cell function by endogenously produced angiotensin II. Am J Physiol Regul Integr Comp Physiol. 2009;296(2):R208–16.

    CAS  PubMed  Google Scholar 

  119. Suematsu M. The inflammatory aspect of the microcirculation in hypertension: oxidative stress, leukocytes/endothelial interaction, apoptosis. Microcirculation. 2002;9:259–76.

    CAS  PubMed  Google Scholar 

  120. Wu L, Iwai M, Nakagami H. Roles of angiotensin II type 2 receptor stimulation associated with selective angiotensin II type 1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury. Circulation. 2001;104:2716–21.

    CAS  PubMed  Google Scholar 

  121. Diep QN, Amiri F, Touyz RM, Cohn JS, Endemann D, Neves MF, et al. PPARa activator effects on Ang II-induced vascular oxidative stress and inflammation. Hypertension. 2002;40:866–71.

    CAS  PubMed  Google Scholar 

  122. Sigmund CD. Endothelial and vascular muscle PPARgamma in arterial pressure regulation: lessons from genetic interference and deficiency. Hypertension. 2010;55(2):437–44.

    CAS  PubMed  Google Scholar 

  123. Tham DM. Angiotensin II, is associated with activation of NF-kappaB-mediated genes and downregulation of PPARs. Physiol Genomics. 2002;11:21–30.

    CAS  PubMed  Google Scholar 

  124. Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease: effects on the cardiovascular system. Circulation. 2007;116(1):85–97.

    PubMed  Google Scholar 

  125. Anand DV, Lim E, Darko D, Bassett P, Hopkins D, Lipkin D, et al. Determinants of progression of coronary artery calcification in type 2 diabetes role of glycemic control and inflammatory/vascular calcification markers. J Am Coll Cardiol. 2007;50(23):2218–25.

    CAS  PubMed  Google Scholar 

  126. Ng K, Hildreth CM, Avolio AP, Phillips JK. Angiotensin-converting enzyme inhibitor limits pulse-wave velocity and aortic calcification in a rat model of cystic renal disease. Am J Physiol Renal Physiol. 2011;301(5):F959–66.

    CAS  PubMed  Google Scholar 

  127. Karwowski W, Naumnik B, Szczepański M. Myśliwiec The mechanism of vascular calcification - a systematic review. Med Sci Monit. 2012;18:1–11.

    Google Scholar 

  128. Tyson KL, Reynolds JL, McNair R, Zhang Q, Weissberg PL, Shanahan CM. Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification. Arterioscler Thromb Vasc Biol. 2003;23:489–94.

    CAS  PubMed  Google Scholar 

  129. Huybers S, Bindels RJ. Vascular calcification in chronic kidney disease: new developments in drug therapy. Kidney Int. 2007;72:663–5.

    CAS  PubMed  Google Scholar 

  130. Li X, Giachelli CM. Sodium-dependent phosphate cotransporters and vascular calcification. Curr Opin Nephrol Hypertens. 2007;16:325–8.

    PubMed  Google Scholar 

  131. Li X, Yang HY, Giachelli CM. BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells. Atherosclerosis. 2008;199:271–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Freedman BI, Bowden DW, Ziegler JT, Langefeld CD, Lehtinen AB, Rudock ME, et al. Bone morphogenetic protein 7 (BMP7) gene polymorphisms are associated with inverse relationships between vascular calcification and BMD: the Diabetes Heart Study. J Bone Miner Res. 2009;24:1719–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Scatena M, Liaw L, Giachelli CM. Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol. 2007;27:2302–9.

    CAS  PubMed  Google Scholar 

  134. Osako MK, Nakagami H, Shimamura M, Koriyama H, Nakagami F, Shimizu H, et al. Cross-Talk of receptor activator of nuclear factor-κB ligand signaling with renin–angiotensin system in vascular calcification. Arterioscler Thromb Vasc Biol. 2013;33:1287–96. In vitro and in vivo studies demonstrate that Ang II induces vascular calcification through pathways that involve receptor activator of nuclear factor-κB ligand (RANKL) and that RANKL itself influences the RAS. These data indicate a circuitous interaction between these systems that amplifies atherogenesis and vascular calcification.

    CAS  PubMed  Google Scholar 

  135. Montezano AC, Zimmerman D, Yusuf H, Burger D, Chignalia AZ, Wadhera V, et al. Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium. Hypertension. 2010;56(3):453–62.

    CAS  PubMed  Google Scholar 

  136. He Y, Yao G, Savoia C, Touyz RM. Transient receptor potential melastatin 7 ion channels regulate magnesium homeostasis in vascular smooth muscle cells: role of angiotensin II. Circ Res. 2005;96(2):207–15.

    CAS  PubMed  Google Scholar 

  137. Jia G, Stormont RM, Gangahar DM, Agrawal DK. Role of matrix Gla protein in angiotensin II-induced exacerbation of vascular calcification. Am J Physiol Heart Circ Physiol. 2012;303(5):H523–32. Demonstration that Ang II influences vascular calcification through processes that interfere with the natural calcification inhibitor, matrix Gla protein and activation of the transcription factors, runt-related transcription factor 2 and NF-κB.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Sui YB, Chang JR, Chen WJ, Zhao L, Zhang BH, Yu YR, et al. Angiotensin-(1-7) inhibits vascular calcification in rats. Peptides. 2013;42:25–34.

    CAS  PubMed  Google Scholar 

  139. Virmani R, Robinowitz M, Geer JC, Breslin PP, Beyer JC, McAllister HA. Coronary artery atherosclerosis revisited in Korean war combat casualties. Arch Pathol Lab Med. 1987;111(10):972–6.

    CAS  PubMed  Google Scholar 

  140. Steinbrecher UP, Parthasarathy S, Leake DS. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of lowdensity lipoprotein phospholipids. Proc Natl Acad Sci U S A. 1984;81:3883–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;16:1832–44.

    Google Scholar 

  142. Nicholson AC, Frieda S, Pearce A, Silverstein RL. Oxidized LDL binds to CD36 on human monocyte-derived macrophages and transfected cell lines. Evidence implicating the lipid moiety of the lipoprotein as the binding site. Arterioscler Thromb Vasc Biol. 1995;15(2):269–75.

    CAS  PubMed  Google Scholar 

  143. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell. 1998;93(2):229–40.

    CAS  PubMed  Google Scholar 

  144. Rios FJ, Ferracini M, Pecenin M, Koga MM, Wang Y, Ketelhuth DF, et al. Uptake of oxLDL and IL-10 production by macrophages requires PAFR and CD36 recruitment into the same lipid rafts. PLoS ONE. 2013;8(10):e76893.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Rios FJ, Koga MM, Pecenin M, Ferracini M, Gidlund M, Jancar S. Oxidized LDL induces alternative macrophage phenotype through activation of CD36 and PAFR. Mediat Inflamm. 2013;2013:198–3.

    Google Scholar 

  146. Libby P, Lichtman AH, Hansson GK. Immune effector mechanisms implicated in atherosclerosis: from mice to humans. Immunity. 2013;38(6):1092–104.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Kiyan Y, Tkachuk S, Hilfiker-Kleiner D, Haller H, Fuhrman B, Dumler I. oxLDL induces inflammatory responses in vascular smooth muscle cells via urokinase receptor association with CD36 and TLR4. J Mol Cell Cardiol. 2014;66:72–82. This study elucidates a novel mechanism contributing to vascular inflammation through the urokinase receptor, which responds to endogenous atherogenic ligands, such as oxLDL, impacting on CD36 and TLR4 function.

    CAS  PubMed  Google Scholar 

  148. Wang YS, Wang HY, Liao YC, Tsai PC, Chen KC, Cheng HY, et al. MicroRNA-195 regulates vascular smooth muscle cell phenotype and prevents neointimal formation. Cardiovasc Res. 2012;95(4):517–26. This interesting study demonstrates that in vascular smooth muscle cells, microRNA-195 reduces proliferation, migration, and synthesis of IL-1β, IL-6, and IL-8. These findings were extended to a rat model where the microRNA-195 gene was introduced by adenovirus, and showed reduced neointimal formation in balloon-injured carotid arteries. Taken together, these data suggest that microRNA-195 may be vasculo-protective.

    CAS  PubMed  Google Scholar 

  149. Hu C, Dandapat A, Mehta JL. Angiotensin II induces capillary formation from endothelial cells via the LOX-1 dependent redox-sensitive pathway. Hypertension. 2007;50:952–7.

    CAS  PubMed  Google Scholar 

  150. Cominacini L, Pasini AF, Garbin U, Davoli A, Tosetti ML, Campagnola M, et al. Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappaB through an increased production of intracellular reactive oxygen species. J Biol Chem. 2000;275(17):12633–8.

    CAS  PubMed  Google Scholar 

  151. Taye A, Saad AH, Kumar AH, Morawietz H. Effect of apocynin on NADPH oxidase-mediated oxidative stress-LOX-1-eNOS pathway in human endothelial cells exposed to high glucose. Eur J Pharmacol. 2010;627:42–8.

    CAS  PubMed  Google Scholar 

  152. Tsai KL, Chen LH, Chiou SH, Chiou GY, Chen YC, Chou HY, et al. Coenzyme Q10 suppresses oxLDL-induced endothelial oxidative injuries by the modulation of LOX-1-mediated ROS generation via the AMPK/PKC/NADPH oxidase signaling pathway. Mol Nutr Food Res. 2011;55:S227–40.

    CAS  PubMed  Google Scholar 

  153. Hu C, Dandapat A, Chen J, Liu Y, Hermonat PL, Carey RM, et al. Over-expression of angiotensin II type 2 receptor (agtr2) reduces atherogenesis and modulates LOX-1, endothelial nitric oxide synthase and heme-oxygenase-1 expression. Atherosclerosis. 2008;199:284–94.

    Google Scholar 

  154. Fukuda D, Enomoto S, Hirata Y, Nagai R, Sata M. The angiotensin receptor blocker, telmisartan, reduces and stabilizes atherosclerosis in ApoE and AT1aR double deficient mice. Biomed Pharmacother. 2010;64(10):712–7.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Studies performed by RMT were supported by grants from the Canadian Institutes of Health Research (CIHR), JDRF and the British Heart Foundation (BHF). RMT is supported through a BHF Chair. ACM is supported by a Leadership fellowship from the University of Glasgow.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rhian M. Touyz.

Ethics declarations

Conflict of Interest Augusto C. Montezano, Aurelie Nguyen Dinh Cat, Francisco J. Rios, and Rhian M. Touyz declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Mediators, Mechanisms, and Pathways in Tissue Injury

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Montezano, A.C., Nguyen Dinh Cat, A., Rios, F.J. et al. Angiotensin II and Vascular Injury. Curr Hypertens Rep 16, 431 (2014). https://doi.org/10.1007/s11906-014-0431-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11906-014-0431-2

Keywords

Navigation