Emerging Aspects of Angiotensin Biology and Their Potential Role in the Vasculature

  • Richard N. ReEmail author
  • Julia L. Cook


Angiotensin II, a major effector protein of the renin-angiotensin, system plays important roles in the regulation of arterial pressure and intravascular volume. In addition, operating at the systemic, tissue, and cellular levels it modifies vascular structure and inflammation, thereby participating in the pathogenesis of hypertension, atherosclerosis, and vascular stiffening. Here recent findings regarding angiotensin II biology and their potential relevance for vascular biology and disease are discussed


Angiotensin Receptors Vascular Biology Intracrine Target Organ Damage 


  1. 1.
    Re RN. New insights into target organ involvement in hypertension. Med Clin North Am. 2009;93:559–67.PubMedCrossRefGoogle Scholar
  2. 2.
    Re RN. The renin-angiotensin systems. Med Clin North Am. 1987;71:877–95.PubMedGoogle Scholar
  3. 3.
    Re RN. Tissue renin angiotensin systems. Med Clin North Am. 2004;88:19–38.PubMedCrossRefGoogle Scholar
  4. 4.
    Re RN. The clinical implication of tissue renin angiotensin systems. Curr Opin Cardiol. 2001;16:317–27.PubMedCrossRefGoogle Scholar
  5. 5.
    Wolf G. Novel aspects of the renin-angiotensin-aldosterone-system. Front Biosci. 2008;13:4993–5005.PubMedCrossRefGoogle Scholar
  6. 6.
    Burchfiel CM, Tracy RE, Chyou PH, et al. Cardiovascular risk factors and hyalinization of renal arterioles at autopsy. The Honolulu Heart Program. Arterioscler Thromb Vasc Biol. 1997;17:760–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Johnson RJ, Alpers CE, Yoshimura A, et al. Renal injury from angiotensin II-mediated hypertension. Hypertension. 1992;19:464–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Schiffrin EL. Vascular remodeling and endothelial function in hypertensive patients: effects of antihypertensive therapy. Scand Cardiovasc J Suppl. 1998;47:15–21.PubMedCrossRefGoogle Scholar
  9. 9.
    Harrison DG, Marvar PJ, Titze JM. Vascular inflammatory cells in hypertension. Front Physiol. 2012;3:128. Epub 2012 May 7.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Harrison DG, Guzik TJ. Studies of the T-cell angiotensin receptor using cre-lox technology: an unan-T-cellpated result. Circ Res. 2012;110:1543–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang JD, Patel MB, Song YS, Griffiths R, Burchette J, Ruiz P, Sparks MA, Yan M, Howell DN, Gomez JA, Spurney RF, Coffman TM, Crowley SD. A novel role for type 1 angiotensin receptors on T lymphocytes to limit target organ damage in hypertension. Circ Res. 2012;110:1604–17.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Strawn WB, Richmond RS, Ann Tallant E, et al. Renin-angiotensin system expression in rat bone marrow haematopoietic and stromal cells. Br J Haematol. 2004;126:120–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Strawn WB, Ferrario CM. Angiotensin II AT1 receptor blockade normalizes CD11b1 monocyte production in bone marrow of hypercholesterolemic monkeys. Atherosclerosis. 2008;196:624–32. Epub 2007 Aug 9.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Re RN. Cellular biology of the renin-angiotensin systems. Arch Intern Med. 1984;144:2037–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Ribichini F, Pugno F, Ferrero V, et al. Cellular immunostaining of angiotensinconverting enzyme in human coronary atherosclerotic plaques. J Am Coll Cardiol. 2006;47:1143–9. Epub 2006 Feb 23.PubMedCrossRefGoogle Scholar
  16. 16.
    Diet F, Pratt RE, Berry GJ, et al. Increased accumulation of tissue ACE in human atherosclerotic coronary disease. Circulation. 1996;94:2756–67.PubMedCrossRefGoogle Scholar
  17. 17.
    Geisterfer AA, Peach MJ, Owens GK. Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res. 1988;62:749–56.PubMedCrossRefGoogle Scholar
  18. 18.
    Campbell-Boswell M, Robertson Jr AL. Effects of angiotensin II and vasopressin on human smooth muscle cells in vitro. Exp Mol Pathol. 1981;35:265–76.PubMedCrossRefGoogle Scholar
  19. 19.
    Levy BI. How to explain the differences between renin angiotensin system modulators. Am J Hypertens. 2005;18(9 Pt 2):134S–41.PubMedCrossRefGoogle Scholar
  20. 20.
    Jones ES, Vinh A, McCarthy CA, et al. AT(2) receptors: functional relevance in cardiovascular disease. Pharmacol Ther. 2008;120:292–316.PubMedCrossRefGoogle Scholar
  21. 21.
    Tang H, Nishishita T, Fitzgerald T, et al. Inhibition of AT1 receptor internalization by concanavalin A blocks angiotensin II-induced ERK activation in vascular smooth muscle cells. Involvement of epidermal growth factor receptor proteolysis but not AT1 receptor internalization. J Biol Chem. 2000;275:13420–6.PubMedCrossRefGoogle Scholar
  22. 22.
    AdbAlla S, Abdel-tawab AM, Quitterer U. The angiotensin II AT2 receptor is an AT1 receptor antagonist. J Biol Chem. 2001;276:39721–6.CrossRefGoogle Scholar
  23. 23.
    AbdAlla S, Lother H, el Massiery A, et al. Increased AT(1) receptor heterodimers in preeclampsia medicate enhanced angiotensin II responsiveness. Nat Med. 2001;7:1003–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Singh BM, Mehta JL. Interactions between the renin-angiotensin system and dyslipidemia: relevance in the therapy of hypertension and coronary heart disease. Arch Intern Med. 2003;163:1296–304.PubMedCrossRefGoogle Scholar
  25. 25.
    Hu C, Dandapat A, Sun L, et al. Modulation of angiotensin II-mediated hypertension and cardiac remodeling by lectin-like oxidized low-density lipoprotein receptor-1 deletion. Hypertension. 2008;52:556–62. Epub 2008 Jul 21.PubMedCrossRefGoogle Scholar
  26. 26.
    Chappel MC, Ferrario CM. ACE and ACE2: their role to balance the expression of angiotensin II and angiotensin-(1–7). Kidney Int. 2006;70:8–10.PubMedCrossRefGoogle Scholar
  27. 27.
    Varagic J, Ahmad S, Brosnihan KB, Groban L, Chappell MC, Tallant EA, Gallagher PE, Ferrario CM. Decreased cardiac Ang-(1–7) is associated with salt-induced cardiac remodeling and dysfunction. Ther Adv Cardiovasc Dis. 2010;4:17–25.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Trask AJ, Ferrario CM. Angiotensin-(1–7): pharmacology and new perspectives in cardiovascular treatments. Cardiovasc Drug Rev. 2007;25:162–74.PubMedCrossRefGoogle Scholar
  29. 29.
    Xue H, Zhou L, Yuan P, Wang Z, Ni J, Yao T, Wang J, Huang Y, Yu C, Lu L. Counteraction between angiotensin II and angiotensin-(1–7) via activating angiotensin type I and Mas receptor on rat renal mesangial cells. Regul Pept. 2012;177:12–20.PubMedCrossRefGoogle Scholar
  30. 30.
    Patel VB, Bodiga S, Fan D, Das SK, Wang Z, Wang W, Basu R, Zhong J, Kassiri Z, Oudit GY. Cardioprotective effects mediated by angiotensin II type 1 receptor blockade and enhancing angiotensin 1–7 in experimental heart failure in angiotensin-converting enzyme 2-null mice. Hypertension. 2012;59:1195–203.PubMedCrossRefGoogle Scholar
  31. 31.
    Fraga-Silva RA, Ferreira AJ, Dos Santos RA. (1–7)/mas receptor pathway in hypertension. Curr Hypertens Rep. 2013;15:31–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Tamura K, Wakui H, Maeda A, Dejima T, Ohsawa M, Azushima K, Kanaoka T, Haku S, Uneda K, Masuda SI, Azuma K, Shigenaga AI, Koide Y, Tsurumi-Ikeya Y, Matsuda M, Toya Y, Tokita Y, Yamashita A, Umemura S. The physiology and pathophysiology of a novel angiotensin receptor-binding protein ATRAP/Agtrap. Curr Pharm Des. 2013;19:3043–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Tsukuda K, Mogi M, Iwanami J, Min LJ, Jing F, Ohshima K, Horiuchi M. Influence of angiotensin II type 1 receptor-associated protein on prenatal development and adult hypertension after maternal dietary protein restriction during pregnancy. J Am Soc Hypertens. 2012;6:324–30.PubMedCrossRefGoogle Scholar
  34. 34.
    Guo DF, Chenier I, Tardif V, Orlov SN, Inagami T. Type 1 angiotensin II receptor-associated protein ARAP1 binds and recycles the receptor to the plasma membrane. Biochem Biophys Res Commun. 2003;310:1254–65.PubMedCrossRefGoogle Scholar
  35. 35.
    Daniele T, Di Tullio G, Santoro M, Turacchio G, De Matteis MA. ARAP1 regulates EGF receptor trafficking and signalling. Traffic. 2008;9:2221–35.PubMedCrossRefGoogle Scholar
  36. 36.
    Cook JL, Re RN, de Haro DL, Abadie JM, Peters M, Alam J. The trafficking protein GABARAP binds to and enhances plasma membrane expression and function of the angiotensin II type 1 receptor. Circ Res. 2008;102:1539–47.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Alam J, Deharo D, Redding KM, Re RN, Cook JL. C-terminal processing of GABARAP is not required for trafficking of the angiotensin II type 1A receptor. Regul Pept. 2010;159:78–86.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Vitko JR, Re RN, Alam J, Cook JL. Cell-penetrating peptides corresponding to the angiotensin II Type 1 receptor reduce receptor accumulation and cell surface expression and signaling. Am J Hypertens. 2012;25:24–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Re RN, Chen B, Alam J, Cook JL. Reduction of blood pressure by AT1 receptor decoy peptides. Ochsner J. 2013;13:33–6.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Cook JL, Mills SJ, Naquin RT, Alam J, Re RN. Cleavage of the angiotensin II type 1 receptor and nuclear accumulation of the cytoplasmic carboxy-terminal fragment. Am J Physiol Cell Physiol. 2007;292:C1313–22. Epub 2006 Nov 22.PubMedCrossRefGoogle Scholar
  41. 41.
    Cook JL, Mills SJ, Naquin R, Alam J, Re RN. Nuclear accumulation of the AT1 receptor in a rat vascular smooth muscle cell line: effects upon signal transduction and cellular proliferation. J Mol Cell Cardiol. 2006;40:696–707. Epub 2006 Mar 6.PubMedCrossRefGoogle Scholar
  42. 42.
    Re RN. Lysosomal action of intracrine angiotensin II. Focus on “Intracellular angiotensin II activates rat myometrium”. Am J Physiol Cell Physiol. 2011;301:C553–4.PubMedCrossRefGoogle Scholar
  43. 43.
    Neri Serneri GG, Boddi M, Coppo M, Chechi T, Zarone N, Moira M, Poggesi L, Margheri M, Simonetti I. Evidence for the existence of a functional cardiac renin-angiotensin system in humans. Circulation. 1996;94:1886–93.PubMedCrossRefGoogle Scholar
  44. 44.
    Frohlich ED, Susic D. Sodium and its multiorgan targets. Circulation. 2011;124:1882–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Re RN. Toward a theory of intracrine hormone action. Regul Pept. 2002;106:1–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Re RN. The intracrine hypothesis and intracellular peptide hormone action. Bioessays. 2003;25:401–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Re RN, Cook JL. The intracrine hypothesis: an update. Regul Pept. 2005;133:1–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Re RN. The implications of intracrine hormone action for physiology and medicine. Am J Physiol Heart Circ Physiol. 2003;284:H751–7.PubMedGoogle Scholar
  49. 49.
    Spatazza J, Di Lullo E, Joliot A, Dupont E, Moya KL, Prochiantz A. Homeoprotein signaling in development, health, and disease: a shaking of dogmas offers challenges and promises from bench to bed. Pharmacol Rev. 2013;65:90–104.PubMedCrossRefGoogle Scholar
  50. 50.
    Dupont E, Prochiantz A, Joliot A. Penetratin story: an overview. Methods Mol Biol. 2011;683:21–9.PubMedCrossRefGoogle Scholar
  51. 51.
    Singh VP, Le B, Bhat VB, et al. High-glucose-induced regulation of intracellular ANG II synthesis and nuclear redistribution in cardiac myocytes. Am J Physiol Heart Circ Physiol. 2007;293:H939–48.PubMedCrossRefGoogle Scholar
  52. 52.
    Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B, Anversa P. Myocardial cell death in human diabetes. Circ Res. 2000;87:1123–32.PubMedCrossRefGoogle Scholar
  53. 53.
    Re RN, Cook JL. Noncanonical intracrine action. J Am Soc Hypertens. 2011;5:435–48.PubMedCrossRefGoogle Scholar
  54. 54.
    Gwathmey TM, Alzayadneh EM, Pendergrass KD, Chappell MC. Novel roles of nuclear angiotensin receptors and signaling mechanisms. Am J Physiol Regul Integr Comp Physiol. 2012;302:R518–30.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Re RN, Vizard DL, Brown J, Bryan SE. Angiotensin II receptors in chromatin fragments generated by micrococcal nuclease. Biochem Biophys Res Commun. 1984;119:220–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Erdmann B, Fuxe K, Ganten D. Subcellular localization of angiotensin II immunoreactivity in the rat cerebellar cortex. Hypertension. 1996;28:818–24.PubMedCrossRefGoogle Scholar
  57. 57.
    Singh VP, Le B, Khode R, Baker KM, Kumar R. Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis. Diabetes. 2008;57:3297–306.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Dikalov SI, Dikalova AE, Bikineyeva AT, Schmidt HH, Harrison DG, Griendling KK. Distinct roles of Nox1 and Nox4 in basal and angiotensin II-stimulated superoxide and hydrogen peroxide production. Free Radic Biol Med. 2008;45:1340–51.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Takeuchi K, Yamamoto K, Ohishi M, Takeshita H, Hongyo K, Kawai T, Takeda M, Kamide K, Kurtz TW, Rakugi H. Telmisartan modulates mitochondrial function in vascular smooth muscle cells. Hypertens Res. 2013;36:433–9. doi: 10.1038/hr.2012.199.
  60. 60.
    Robertson Jr AL, Khairallah PA. Angiotensin II: rapid localization in nuclei of smooth and cardiac muscle. Science. 1971;172:1138–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Goodfriend TL, Fyhrquist F, Gutmann F, Knych E, Hollemans H, Allmann D, Kent K, Cooper T. Clinical and conceptual uses of angiotensin receptors. In: Genest J, Koiw E, editors. Hypertension '72. Berlin: Springer; 1972. p. 549–63.Google Scholar
  62. 62.
    Husain K, Suarez E, Isidro A, Ferder L. Effects of paricalcitol and enalapril on atherosclerotic injury in mouse aortas. Am J Nephrol. 2010;32:296–304.PubMedCrossRefGoogle Scholar
  63. 63.
    Abadir PM, Foster DB, Crow M, Cooke CA, Rucker JJ, Jain A, Smith BJ, Burks TN, Cohn RD, Fedarko NS, Carey RM, O’Rourke B, Walston JD. Identification and characterization of a functional mitochondrial angiotensin system. Proc Natl Acad Sci U S A. 2011;108:14849–54.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    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;55:166–71.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Cook JL, Zhang Z, Re RN. In vitro evidence for an intracellular site of angiotensin action. Circ Res. 2001;89:1138–46.PubMedCrossRefGoogle Scholar
  66. 66.
    Cook JL, Giardina JF, Zhang Z, Re RN. Intracellular angiotensin II increases the long isoform of PDGF mRNA in rat hepatoma cells. J Mol Cell Cardiol. 2002;34:1525–37.PubMedCrossRefGoogle Scholar
  67. 67.
    Redding KM, Chen BL, Singh A, Re RN, Navar LG, Seth DM, Sigmund CD, Tang WW, Cook JL. Transgenic mice expressing an intracellular fluorescent fusion of angiotensin II demonstrate renal thrombotic microangiopathy and elevated blood pressure. Am J Physiol Heart Circ Physiol. 2010;298:H1807–18.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Cook JL, Re RN. Lessons from in vitro studies and a related intracellular angiotensin II transgenic mouse model. Am J Physiol Regul Integr Comp Physiol. 2012;302:R482–93.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Re RN, Cook JL. The mitochondrial component of intracrine action. Am J Physiol Heart Circ Physiol. 2010;299:H577–83.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2014

Authors and Affiliations

  1. 1.Research DivisionOchsner Health SystemNew OrleansUSA

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