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The role of angiotensin II in regulating vascular structural and functional changes in hypertension

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Abstract

A major hemodynamic abnormality in hypertension is increased peripheral resistance due to changes in vascular structure and function. Structural changes include reduced lumen diameter and arterial wall thickening. Functional changes include increased vasoconstriction and/or decreased vasodilation. These processes are influenced by many humoral factors, of which angiotensin II (Ang II) seems to be critical. At the cellular level, Ang II stimulates vascular smooth muscle cell growth, increases collagen deposition, induces inflammation, increases contractility, and decreases dilation. Molecular mechanisms associated with these changes in hypertension include upregulation of many signaling pathways, including tyrosine kinases, mitogen-activated protein kinases, RhoA/Rho kinase, and increased generation of reactive oxygen species. This review focuses on the role of Ang II in vascular functional and structural changes of small arteries in hypertension. In addition, cellular processes whereby Ang II influences vessels in hypertension are discussed. Finally, novel concepts related to signaling pathways by which Ang II regulates vascular smooth muscle cells in hypertension are introduced.

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References and Recommended Reading

  1. Korner PI, Bobik A, Angus JA, et al.: Resistance control in hypertension. J Hypertens 1989, 7:S125-S134.

    CAS  Google Scholar 

  2. Cain AE, Khalil RA: Pathophysiology of essential hyperension: role of the pump, the vessel and the kidney. Semin Nephrol 2002, 22:3–16.

    PubMed  CAS  Google Scholar 

  3. Intengan HD, Schiffrin EL: Vascular remodeling in hypertension. Roles of apoptosis, inflammation and fibrosis. Hypertension 2002, 38:581–587.

    Google Scholar 

  4. Mulvany MJ: Small artery remodeling in hypertension. Curr Hypertens Rep 2002, 4:49–55.

    PubMed  Google Scholar 

  5. Berk BC: Vascular smooth muscle growth: autocrine growth mechanisms. Physiol Rev 2002, 81:999–1030. A comprehensive review on processes regulating vascular smooth muscle cell growth.

    Google Scholar 

  6. Wesselman JPM, De Mey JGR: Angiotensin and cytoskeletal proteins: role in vascular remodeling. Curr Hypertens Rep 2002, 4:63–70.

    PubMed  Google Scholar 

  7. Intengan HD, Schiffrin EL: Structure and mechanical properties of resistance arteries in hypertension: role of adhesion molecules and extracellular matrix determinants. Hypertension 2000, 36:312–318.

    PubMed  CAS  Google Scholar 

  8. Brasier AR, Recinos A, Eledrisi MS: Vascular inflammation and the renin angiotensin system. Arterioscler Thromb Vasc Biol 2002, 22:1257–1266. An excellent review on the proinflammatory role of Ang II in the vasculature.

    Article  PubMed  CAS  Google Scholar 

  9. Taylor RW: Hypertensive vascular disease and inflammation: mechanical and humoral mechanisms. Curr Hypertens Rep 1999, 1:96–101.

    PubMed  CAS  Google Scholar 

  10. Touyz RM, Schiffrin EL: Signal transduction mechanisms mediating the physiological and pathophysiological actions of Ang II in vascular smooth muscle cells. Pharmacol Rev 2000, 52:639–672.

    PubMed  CAS  Google Scholar 

  11. Tschope C, Schultheiss H-P, Walther T: Multiple interactions between the renin-angiotensin and the kallikrein-kinin systems: role of ACE inhibition and AT1 receptor blockade. J Cardiovasc Pharmacol 2002, 39:478–487.

    Article  PubMed  CAS  Google Scholar 

  12. Berry C, Touyz R, Dominiczak AF, et al.: Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide. Am J Physiol Heart Circ Physiol 2001, 281:H2337-H2365.

    PubMed  CAS  Google Scholar 

  13. Stoll M, Unger T: Angiotensin and its AT2 receptor: new insights into an old system. Regul Pept 2001, 99:175–182.

    Article  PubMed  CAS  Google Scholar 

  14. Schiffrin EL, Park JB, Intengan HD, Touyz RM: Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation 2000, 101:1653–1659.

    PubMed  CAS  Google Scholar 

  15. Schiffrin EL: Correction of remodeling and function of small arteries in human hypertension by cilazapril, an angiotensin 1-converting enzyme inhibitor. J Cardiovasc Pharmacol 1996, 27(Suppl 2):S13-S18.

    Article  PubMed  CAS  Google Scholar 

  16. Hernandez-Hernandez R, Sosa-Canache B, Velasco M, et al.: Angiotensin II receptor antagonists role in arterial hypertension. J Hum Hypertens 2002, 16:S93-S99.

    Article  PubMed  CAS  Google Scholar 

  17. Spieker LE, Noll G, Ruschitzka FT, et al.: Working under pressure: the vascular endothelium in arterial hypertension. J Hum Hypertens 2000, 14:617–630.

    Article  PubMed  CAS  Google Scholar 

  18. Schiffrin EL, Touyz RM: Vascular biology of endothelin. J Cardiovasc Pharmacol 1998, 32:S2-S13.

    PubMed  CAS  Google Scholar 

  19. Schiffrin EL, Deng LY: Comparison of effects of angiotensin Iconverting enzyme inhibition and beta blockade on function of small arteries from hypertensive patients. Hypertension 1995, 25(part 2):699–703.

    PubMed  CAS  Google Scholar 

  20. Muiesan ML, Rizzoni D, Salvetti M, et al.: Structural changes in small resistance arteries and left ventricular geometry in patients with primary and secondary hypertension. J Hypertens 2002, 20:1439–1444.

    Article  PubMed  CAS  Google Scholar 

  21. Schiffrin EL, Larivière R, Li JS, et al.: DOCA plus salt induces overexpression of vascular ET-1 and severe vascular hypertrophy in SHR. Hypertension 1995, 25:769–773.

    PubMed  CAS  Google Scholar 

  22. Mulvany MJ, Baandrup U, Gundersen HJG: Evidence for hyperplasia in mesenteric resistance vessels of spontaneously hypertensive rats using a three-dimensional dissector. Circ Res 1985, 57:794–800.

    PubMed  CAS  Google Scholar 

  23. Gibbons GH, Pratt RE, Dzau VJ: Vascular smooth muscle cell hypertrophy vs hyperplasia. J Clin Invest 1992, 90:456–461.

    Article  PubMed  CAS  Google Scholar 

  24. Nishijo N, Takamine S, Sugiyama F, et al.: Vascular remodeling in hypertensive transgenic mice. Exp Anim 1999, 48:203–208.

    Article  PubMed  CAS  Google Scholar 

  25. Hu W-Y, Fukuda N, Kanmatsuse K: Growth characteristics, angiotensin II generation and microarray-determined gene expression in vascular smooth muscle cells from young spontaneously hypertensive rats. J Hypertens 2002, 20:1323–1333. This study identifies genes that are differentially expressed in vascular smooth muscle cells from SHR and Wistar Kyoto rats, and demonstrates that these differences are genetically determined rather than blood pressure determined.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  27. Touyz RM, Schiffrin EL: Activation of the Na+/H+ exchanger modulates angiotensin II-stimulated Na+-dependent Mg2+ transport in vascular smooth muscle cells from spontaneously hypertensive rats. Hypertension 1999, 34:442–449.

    PubMed  CAS  Google Scholar 

  28. Amman K, Ghareehbaghi H, Stephens S, Mall G: Hypertrophy and hyperplasia of smooth muscle cells of small intramyocardial arteries in SHR. Hypertension 1995, 25:124–131.

    Google Scholar 

  29. Simon G, Illyes G, Csiky B: Structural vascular changes in hypertension. Role of angiotensin II, dietary sodium supplementation, blood pressure and time. Hypertension 1998, 32:654–660.

    PubMed  CAS  Google Scholar 

  30. Dickhout JG, Lee RM: Structural and functional analysis of small arteries from young SHR. Hypertension 1997, 29:781–789.

    PubMed  CAS  Google Scholar 

  31. Rizzoni D, Porteri E, Piccoli A, et al.: Effects of losartan and enalapril on small artery structure in hypertensive rats. Hypertension 1998, 32:305–310.

    PubMed  CAS  Google Scholar 

  32. Dickhout JG, Lee RM: Apoptosis in the muscular arteries from young SHR. J Hypertens 1999, 17:1413–1419.

    Article  PubMed  CAS  Google Scholar 

  33. Diep QN, Li JS, Schiffrin EL: In vivo study of AT1 and AT2 antagangiotensin receptors in apoptosis of rat blood vessels. Hypertension 1999, 34:617–624.

    PubMed  CAS  Google Scholar 

  34. Sharifi AM, Schiffrin EL: Apoptosis in vasculature of SHR:effects of an angiotensin-converting enzyme inhibitor and a calcium channel antagonist. Am J Hypertens 1998, 11:1108–1116.

    Article  PubMed  CAS  Google Scholar 

  35. Wu L, Iwai M, Nakagami H, et al.: Effect of Ang II type 1 receptor blockade on cardiac remodeling in Ang II type 2 receptor null mice. Arterioscler Thromb Vasc Biol 2002, 22:49–54.

    Article  PubMed  Google Scholar 

  36. Tea BS, Der Sarkissian S, Touyz RM, et al.: Proapoptotic and growth-inhibitory role of angiotensin II type 2 receptor in vascular smooth muscle cells from SHR in vivo. Hypertension 2000, 35:1069–1073.

    PubMed  CAS  Google Scholar 

  37. deBlois D, Orlov SN, Hamet P: Apoptosis in cardiovascular remodeling-effect of medication. Cardiovasc Drugs Ther 2001, 15:539–545.

    Article  PubMed  CAS  Google Scholar 

  38. Risler N, Castro C, Cruzado M, et al.: Early changes in proteoglycans production by resistance arteries smooth muscle cells of hypertensive rats. Am J Hypertens 2002, 15:416–421.

    Article  PubMed  CAS  Google Scholar 

  39. Intengan HD, Deng LY, Li JS, Schiffrin EL: Mechanics and composition of human subcutaneous resistance arteries in essential hypertension. Hypertension 1999, 33:569–574.

    PubMed  CAS  Google Scholar 

  40. Delva P, Lechi A, Pastori A, et al.: Collagen I and III mRNA gene expression and cell growth potential of skin fibroblasts in patients with essential hypertension. J Hypertens 2002, 20:1393–1399.

    Article  PubMed  CAS  Google Scholar 

  41. Rossi GP, Cavallin M, Belloni AS, et al.: Aortic smooth muscle cell phenotypic modulation and fibrillar collagen deposition in angiotensin II-dependent hypertension. Cardiovasc Res 2002, 55:178–189.

    Article  PubMed  CAS  Google Scholar 

  42. Touyz RM, He G, El Mabrouk M, et al.: Differential activation of extracellular signal-regulated protein kinase 1/2 and p38 mitogen activated-protein kinase by AT1 receptors in vascular smooth muscle cells from Wistar-Kyoto rats and spontaneously hypertensive rats. J Hypertens 2001, 19:553–559.

    Article  PubMed  CAS  Google Scholar 

  43. Intengan DH, Schiffrin EL: Collagen degradation is diminished in mesenteric arteries of SHR after hypertension is established. Hypertension 1999, 34:329A.

    Google Scholar 

  44. Varo N, Iraburu MJ, Varela M, et al.: Chronic AT1 blockade stimulates extracellular collagen type I degradation and reverses myocardial fibrosis in SHR. Hypertension 2000, 35:1197–1202.

    PubMed  CAS  Google Scholar 

  45. Bhatt DL, Topol EJ: Need to test the arterial inflammation hypothesis. Circulation 2002, 106:136–140.

    Article  PubMed  Google Scholar 

  46. Abe J-I, Berk BC: Reactive oxygen species of signal transduction in cardiovascular disease. Trends Cardiovasc Med 1998, 8:59–64.

    Article  CAS  Google Scholar 

  47. Griendling KK, Sorescu D, Lassegue B, Ushio-Fukai M: Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol 2000, 20:2175–2183. This is an outstanding overview of signaling pathways regulated by reactive oxygen species, and the implications in vascular damage in hypertension.

    PubMed  CAS  Google Scholar 

  48. Yoon SO, Park SJ, Yoon SY, et al.: Sustained production of H(2)O(2) activates pro-matrix metalloproteinase-2 through receptor tyrosine kinases/phosphatidylinositol 3-kinase/ NF-kappa B pathway. J Biol Chem 2002, 277:30271–30282. An in-depth study demonstrating that MMP is regulated by redoxsensitive pathways.

    Article  PubMed  CAS  Google Scholar 

  49. Pueyo ME, Gonzalez W, Nicoletti A, et al.: Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via NFkB activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol 2000, 20:645–651.

    PubMed  CAS  Google Scholar 

  50. Navalkar S, Parthasarathy S, Santanam N, Khan BV: Irbesartan, an angiotensin type 1 receptor inhibitor, regulates markers of inflammation in patients with premature atherosclerosis. J Am Coll Cardiol 2001, 37:440–444.

    Article  PubMed  CAS  Google Scholar 

  51. Touyz RM, Tolloczko B, Schiffrin EL: Mesenteric vascular smooth muscle cells from spontaneously hypertensive rats display increased calcium responses to angiotensin II but not to endothelin-1. J Hypertens 1994, 12:663–673.

    PubMed  CAS  Google Scholar 

  52. Schiffrin EL, Deng LY, Larochelle P: Morphology of resistance arteries and comparison of effects of vasoconstrictors in mild essential hypertensive patients. Clin Invest Med 1993, 22:523–526.

    Google Scholar 

  53. Touyz RM, El Mabrouk M, Schiffrin EL: MEK inhibition attenuates Ang II-mediated signaling and contraction in SHR vascular smooth muscle cells. Circ Res 1999, 84:505–515.

    PubMed  CAS  Google Scholar 

  54. van Geel PP, Pinto YM, Voors AA, et al.: Angiotensin II type 1 receptor A1166C polymorphism is associated with an increased response to angiotensin II in human arteries. Hypertension 2000, 35:717–721.

    PubMed  Google Scholar 

  55. Dendorfer A, Thornagel A, Raasch W, et al.: Angiotensin II induces catecholamine release by direct ganglionic excitation. Hypertension 2002, 40:348–354.

    Article  PubMed  CAS  Google Scholar 

  56. Chitaley K, Weber DS, Webb RC: RhoA/Rho kianse, vascular changes and hypertension. Curr Hypertens Rep 2001, 3:139–144.

    PubMed  CAS  Google Scholar 

  57. Stanke-Labesque F, Devillier P, Veitl S, et al.: Cysteinyl leukotrienes are involved in angiotensin II-induced contraction of aorta from SHR. Cardiovasc Res 2001, 49:152–160.

    Article  PubMed  CAS  Google Scholar 

  58. Imig JD, Zhao X, Capdevila JH, et al.: Soluble epoxide hydrolase inhibition lowers arterial blood pressure in angiotensin II hypertension. Hypertension 2002, 39:690–694.

    Article  PubMed  CAS  Google Scholar 

  59. Puddu P, Puddu GM, Zaca F, Muscari A: Endothelial dysfunction in hypertension. Acta Cardiologica 2000, 55:221–232.

    Article  PubMed  CAS  Google Scholar 

  60. Touyz RM: Impaired vasorelaxation in hypertension: beyond the endothelium. J Hypertens 2002, 20:463–470.

    Article  Google Scholar 

  61. Bragulat E, de la Sierra A, Antonio MT, Coca A: Endothelial dysfunction in salt-sensitive essential hypertension. Hypertension 2001, 37:444–448.

    PubMed  CAS  Google Scholar 

  62. Mukai Y, Shimokawa H, Higashi M, et al.: Inhibition of the renin-angiotensin system ameliorates endothelial dysfunction associated with aging in rats. Arterioscler Thromb Vasc Biol 2002, 22:1445–1450. This in vivo study clearly demonstrates the importance of the reninangiotensin system in endothelial function.

    Article  PubMed  CAS  Google Scholar 

  63. Cai H, Harrison D: Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000, 87:840–844.

    PubMed  CAS  Google Scholar 

  64. Schiffrin EL: Beyond blood pressure: the endothelium and atherosclerosis progression. Am J Hypertens 2002, 15:S115-S122.

    Article  Google Scholar 

  65. Feldman RD, Gros R: Impaired vasodilator function in hypertension. The role of alterations in receptor-G protein coupling. Trends Cardiovasc Med 1998, 8:297–305.

    Article  PubMed  CAS  Google Scholar 

  66. Cardillo C, Kilcoyne CM, Quyyumi AA, et al.: Decreased vasodilation response to isoproterenol during nitric oxide inhibition in humans. Hypertension 1997, 30:918–921.

    PubMed  CAS  Google Scholar 

  67. Lopez-Farre A, Rodrguez-Feo JA, Garcia-Colis E, et al.: Reduction of the soluble cyclic GMP vasorelaxing system in the vawscular wall of the stroke-prone spontaneously hypertensive rats. Effects of the a1-receptor blocker doxazosin. J Hypertens 2002, 20:463–470.

    Article  PubMed  CAS  Google Scholar 

  68. Touyz RM, Wu XH, He G, et al.: Increased angiotensin IImediated 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(2 Pt 2):479–485.

    Article  PubMed  CAS  Google Scholar 

  69. Schieffer B, Paxton WG, Marrero MB, Bernstein KE: Importance of tyrosine phosphorylation in angiotensin II type 1 receptor signaling. Hypertension 1996, 27:476–480.

    PubMed  CAS  Google Scholar 

  70. Ushio-Fukai M, Alexander RW, Akers M, Griendling KK: p38 Mitogen-activated protein kinase is a critical component of the redox-sensitive signaling pathways activated by angiotensin II. Role in vascular smooth muscle cell hypertrophy. J Biol Chem 1998, 271:15022–15029.

    Article  Google Scholar 

  71. Touyz RM, Deschepper C, Park JB, et al.: Inhibition of mitogen-activated protein/extracellular signal-regulated kinase improves endothelial function and attenuates Ang II-induced contractility of mesenteric resistance arteries from spontaneously hypertensive rats. J Hypertens 2002, 20:1127–1134.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  73. Touyz RM, Chen X, He G, et al.: Expression of a gp91phoxcontaining leukocyte-type NADPH oxidase in human vascular smooth muscle cells - modulation by Ang II. Circ Res 2002, 90:1205–1213. The first study to demonstrate that human vascular smooth muscle cells from resistance arteries possess phagocytic NAD(P)H oxidase subunits.

    Article  PubMed  CAS  Google Scholar 

  74. Griendling KK, Sorescu D, Ushio-Fukai M: NADPH oxidase. Role in cardiovascular biology and disease. Circ Res 2000, 86:494–501.

    PubMed  CAS  Google Scholar 

  75. Laursen JB, Rajagopalan S, Galis Z, et al.: Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation 1997, 95:588–593.

    PubMed  CAS  Google Scholar 

  76. Chen X, Touyz RM, Park JB, Schiffrin EL: Antioxidant effects of vitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. Hypertension 2001, 38(3 Pt 2):606–611.

    PubMed  CAS  Google Scholar 

  77. Diep QN, El Mabrouk M, Cohn JS, et al.: Structure, endothelial function, cell growth and inflammation in blood vessels of angiotensin II-infused rats. Role of peroxisome proliferatoractivated receptor-g. Circulation 2002, 105:2296–2302. An important study demonstrating the role of vascular inflammation in Ang II-dependent hypertension and the association with PPARã.

    Article  PubMed  CAS  Google Scholar 

  78. Lounsbury KM, Hu Q, Ziegelstein RC: Calcium signaling and oxidant stress in the vasculature. Free Radic Biol Med 2000, 28:1362–1369.

    Article  PubMed  CAS  Google Scholar 

  79. Uehata M, Ishizaki T, Satoh H, et al.: Calcium sensitization of smooth muscle mediated by Rho-associated protein kinase in hypertension. Nature 1996, 389:990–994.

    Article  Google Scholar 

  80. Masumoto A, Hirooka Y, Shimokawa H, et al.: Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertension 2001, 38:1307–1310.

    PubMed  CAS  Google Scholar 

  81. Funakoshi Y, Ichiki T, Shimokawa H, et al.: Rho-kinase mediates angiotensin II-induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells. Hypertension 2001, 38:100–104.

    PubMed  CAS  Google Scholar 

  82. Kobayashi N, Nakano S, Mita S-I, et al.: Involvement of Rho-kinase pathway for Ang II-induced plasminogen activator inhibitor gene expression and cardiovascular remodeling in hypertensive rats. J Pharmacol Exp Ther 2002, 301:459–466.

    Article  PubMed  CAS  Google Scholar 

  83. Kataoka C, Egashira K, Inoue S, et al.: Important role of Rho-kinase in the pathogenesis of cardiovascular unflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats. Hypertension 2002, 39:245–250.

    Article  PubMed  CAS  Google Scholar 

  84. Yusuf S, Sleight P, Pogue J, et al., for the Heart Outcomes Prevention Evaluation Study Investigators: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000, 342:145–153. A major clinical study demonstrating the beneficial effects of ACE inhibitors and AT1R blockers on cardiovascular outcomes.

    Article  PubMed  CAS  Google Scholar 

  85. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, for the LIFE Study Group: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002, 359:995–1003. Another major clinical study demonstrating the beneficial effects of ACE inhibitors and AT1R blockers on cardiovascular outcomes.

    Article  PubMed  CAS  Google Scholar 

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Touyz, R.M. The role of angiotensin II in regulating vascular structural and functional changes in hypertension. Current Science Inc 5, 155–164 (2003). https://doi.org/10.1007/s11906-003-0073-2

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