Skip to main content

Advertisement

Log in

Molecular mechanisms of angiotensin II-induced vascular injury

  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Blockers of the renin-angiotensin system are used in the treatment of several cardiovascular and renal diseases, including hypertension, atherosclerosis, and cardiac failure. Angiotensin II plays an essential role in the pathogenesis of these diseases through the regulation of cell growth, inflammation, and fibrosis. There are two main angiotensin II receptors, AT1 and AT2. The AT1 receptor is responsible for most of the pathophysiologic actions of angiotensin II, including cell proliferation, production of growth factors and cytokines, and fibrosis. AT2 causes antiproliferation and counteracts the cell growth induced by AT1 activation. We review the mechanisms whereby AT1 and AT2 receptors elicit their respective actions. We discuss the current understanding of the signaling mechanisms involved in angiotensin II-induced vascular damage, describing the mediators (growth factors and cytokines) and intracellular signals (activation of protein kinases, transcription factors, and redox pathways) implicated in these processes, with special emphasis on novel information and open questions.

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.

Similar content being viewed by others

References and Recommended Reading

  1. de Gasparo M, Catt KJ, Inagami T, et al.: International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 2000, 52:415–472. A complete review of Ang II receptors, describing their distribution, signaling mechanisms, and functions.

    PubMed  Google Scholar 

  2. Ruiz-Ortega M, Lorenzo O, Suzuki Y, et al.: Proinflammatory actions of angiotensins. Curr Opin Nephrol Hypertens 2001, 10:321–329. This paper reviews the novel view of Ang II as proinflammatory mediator, summarizing all the information available in inmmune and inflammatory diseases, and discussing the molecular mechanism of Ang II action and its role to inflammatory responses that contribute to the pathogenesis of cardiovascular and renal diseases.

    Article  PubMed  CAS  Google Scholar 

  3. Itoh H, Mukoyama M, Pratt RE, et al.: Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin II. J Clin Invest 1993, 91:2268–2274.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  5. 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 of spontaneously hypertensive rats in vivo. Hypertension 2000, 35:1069–1073.

    PubMed  CAS  Google Scholar 

  6. Mezzano S, Ruiz-Ortega M, Egido J: Angiotensin II and renal fibrosis. Hypertension 2001, 38:635–638.

    PubMed  CAS  Google Scholar 

  7. Brede M, Hein L: Transgenic mouse models of angiotensin receptor subtype function in the cardiovascular system. Regul Pept 2001, 96:125–132.

    Article  PubMed  CAS  Google Scholar 

  8. Lombardi DM, Viswanathan M, Vio CP, et al.: Renal and vascular injury induced by exogenous angiotensin II is AT1 receptor-dependent. Nephron 2001, 87:66–74.

    Article  PubMed  CAS  Google Scholar 

  9. Ford CM, Li S, Pickering JG: Angiotensin II stimulates collagen synthesis in human vascular smooth muscle cells. Involvement of the AT1 receptor, transforming growth factorβ, and tyrosine phosphorylation. Arterioscler Thromb Vasc Biol 1999, 19:1843–1851.

    PubMed  CAS  Google Scholar 

  10. Ruiz-Ortega M, Egido J: Angiotensin II modulates cell growthrelated events and synthesis of matrix proteins in renal interstitial fibroblasts. Kidney Int 1997, 52:1497–1510.

    Article  PubMed  CAS  Google Scholar 

  11. Mifune M, Sasamura H, Shimizu-Hirota R, et al.: Angiotensin II type 2 receptors stimulate collagen synthesis in cultured vascular smooth muscle cells. Hypertension 2000, 36:845–850.

    PubMed  CAS  Google Scholar 

  12. Li JS, Touyz RM, Schiffrin EL: Effects of AT1 and AT2 angiotensin receptor antagonists in angiotensin II-infused rats. Hypertension 1998, 31:487–492.

    PubMed  CAS  Google Scholar 

  13. Levy BI, Bennessiano J, Henrion D, et al.: Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure. J Clin Invest 1996, 98:418–425.

    PubMed  CAS  Google Scholar 

  14. Laviades C, Varo N, Fernandez J, et al.: Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation 1998, 98:535–540.

    PubMed  CAS  Google Scholar 

  15. Nakamura S, Nakamura I, Ma L, et al.: Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo. Kidney Int 2000, 58:251–259.

    Article  PubMed  CAS  Google Scholar 

  16. Border WA, Noble NA: Interactions of transforming growth factor-b and angiotensin II in renal fibrosis. Hypertension 1998, 31:181–188.

    PubMed  CAS  Google Scholar 

  17. Lau LF, Lam SCT: The CCN family of angiogenic regulators: The integrin connection. Exp Cell Res 1999, 248:44–57.

    Article  PubMed  CAS  Google Scholar 

  18. Rupérez M, Lorenzo O, Blanco-Colio L, et al.: Intracelular signals invoved in angiotensin II-induced fibrosis in vascular damage. Description of a new mediator: the connective tissue growth factor. Circulation 2001, 104:179.

    Google Scholar 

  19. Rupérez M, Lorenzo O, Egido J, Ruiz-Ortega M: Angiotensin II increases connective tissue growth factor in the kidney. J Am Soc Nephrol 2001, 12:471A.

    Google Scholar 

  20. Massfelder T, Taesch N, Endlich N, et al.: Paradoxical actions of exogenous and endogenous parathyroid hormone-related protein on renal vascular smooth muscle cell proliferation: reversion in the SHR model of genetic hypertension. FASEB J 2001, 15:707–718.

    Article  PubMed  CAS  Google Scholar 

  21. Lorenzo O, Ruiz-Ortega M, Esbrit P, et al.: Modulation of parathyroid hormone (PTH)-related protein (PTHRP) and the PTH/PHJRP receptor-1 by angiotensin ii in the rat kidney. J Am Soc Nephrol 2002, 13:1595–1607.

    Article  PubMed  CAS  Google Scholar 

  22. Ruiz-Ortega M, Ruperez M, Lorenzo O, et al.: Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int 2002, In press.

  23. Levine B, Kalman J, Mayer L, et al.: Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990, 323:236–241.

    Article  PubMed  CAS  Google Scholar 

  24. Yokoyama T, Sekiguchi K, Tanaka T, et al.: Angiotensin II and mechanical stretch induce production of tumor necrosis factor in cardiac fibroblasts Am J Physiol 1999, 276:H1968-H1976.

    PubMed  CAS  Google Scholar 

  25. Barath P, Fishbein MC, Cao J, et al.: Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol 1990, 65:297–302.

    Article  PubMed  CAS  Google Scholar 

  26. Tharaux PL, Chatzaiantoniou C, Fakhouri F, Dussaule JC: Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. Hypertension 2000, 36:330–336. An interesting original paper describing the molecular mechanism involved in Ang II-induced collagen regulation.

    PubMed  CAS  Google Scholar 

  27. Verrecchia F, Mauviel A: Control of connective tissue gene expression by TGF beta: role of Smad proteins in fibrosis. Curr Rheumatol Rep 2002, 4:143–149.

    PubMed  Google Scholar 

  28. Hao J, Wang B, Jones SC, et al.: Interaction between angiotensin II and Smad proteins in fibroblasts in failing heart and in vitro. Am J Physiol Heart Circ Physiol 2000, 279:H3020–3030.

    PubMed  CAS  Google Scholar 

  29. Hayashida T, Poncelet AC, Hubchak SC, Schnapper HW: TGF-β1 activates MAP kinase in human mesangial cells: a possible role in collagen expression. Kidney Int 1999, 56:1710–1720.

    Article  PubMed  CAS  Google Scholar 

  30. Moriguchi Y, Matsubara H, Mori Y, et al.: Angiotensin IIinduced transactivation of epidermal growth factor receptor regulates fibronectin and transforming growth factor-beta synthesis via transcriptional and posttranscriptional mechanisms. Circ Res 1999, 84:1073–1084.

    PubMed  CAS  Google Scholar 

  31. Treisman R: Regulation of transcription by MAP kinase cascades. Curr Opin Cell Biol 1996, 8:205–215.

    Article  PubMed  CAS  Google Scholar 

  32. Deguchi J, Makuuchi M, Nakaoka T, et al.: Angiotensin II stimulates platelet-derived growth factor-B chain expression in newborn rat vascular smooth muscle cells and neointimal cells through Ras, extracellular signal-regulated protein kinase, and c-Jun N-terminal protein kinase mechanisms. Circ Res 1999, 85:565–574.

    PubMed  CAS  Google Scholar 

  33. Tamura K, Nyui N, Tamura N, et al.: Mechanism of angiotensin II-mediated regulation of fibronectin gene in rat vascular smooth muscle cells. Biol Chem 1998, 273:26487–26496.

    Article  CAS  Google Scholar 

  34. Nahman NS, Rothe KL, Falkenhain ME, et al.: Angiotensin II induction of fibronectin biosynthesis in cultured human mesangial cells: association with CREB transcription factor activation. J Lab Clin Med 1996, 127:599–611.

    Article  PubMed  CAS  Google Scholar 

  35. Aoki H, Izumo S, Sadoshima J: Angiotensin II activates RhoA in cardiac myocytes: a critical role of RhoA in angiotensin IIinduced premyofibril formation. Circ Res 1998, 82:666–676.

    PubMed  CAS  Google Scholar 

  36. Johns DG, Dorrance AM, Leite R, et al.: Novel signaling pathways contributing to vascular changes in hypertension. J Biomed Sci 2000, 7:431–433. This paper reviews the cellular signaling pathways involved in vascular changes in hypertension, in particular the role of Rho/Rho kinase.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  38. Rupérez M, Blanco-Colio L, Lorenzo O, et al.: HMG-CoA reductase inhibitors regulate angiotensin II responses via rho proteins: modulation of connective tissue growth factor in vascular smooth muscle cells. Circulation 2002, In press.

  39. Griendling KK, Ushio-Fukai M: Reactive oxygen species as mediators of angiotensin II signaling. Regul Pept 2000, 91:21–27.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  41. Schneider A, Panzer U, Zahner G, et al.: Monocyte chemoattractant protein-1 mediates collagen deposition in experimental glomerulonephritis by transforming growth factor-b. Kidney Int 1999, 56:135–144.

    Article  PubMed  CAS  Google Scholar 

  42. Ortiz LA, Champion HC, Lasky JA, et al.: Enalapril protects mice from pulmonary hypertension by inhibiting TNF-mediated activation of NF-kappaB and AP-1. Am J Physiol Lung Cell Mol Physiol 2002, 282:L1209-L1221.

    PubMed  CAS  Google Scholar 

  43. Muller DN, Dechend R, Mervaala EM, et al.: NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension 2000, 35:193–201.

    PubMed  CAS  Google Scholar 

  44. Lorenzo O, Rupérez M, Esteban V, et al.: The AT2 receptor participates in the inflammatory cell recruitment during kidney damage. Role of NF-kB pathway. J Am Soc Nephrol 2002, 13:346.

    Article  CAS  Google Scholar 

  45. Ruiz-Ortega M, Lorenzo O, Ruperez M, et al.: Role of AT1 and AT2 receptors in angiotensin II-induced nuclear transcription factor kB activation in vascular smooth muscle cells. Circ Res 2000, 86:1266–1272. First paper describing the role of AT2 receptors in Ang II-induced NF-βB and the associated molecular mechanisms.

    PubMed  CAS  Google Scholar 

  46. Ruiz-Ortega M, Lorenzo O, Ruperez M, et al.: Systemic infusion of angiotensin II into normal rats activates nuclear factor k-b and Ap-1 in the kidney. Role of AT1 and AT2 receptors. Am J Pathol 2001, 158:1743–1756.

    PubMed  CAS  Google Scholar 

  47. Wolf G, Hannaken T, Burs K, et al.: Angiotensin II activates the NF-kB pathway through AT2 receptors. J Am Soc Nephrol 2000, 11:430.

    Google Scholar 

  48. Ruiz-Ortega M, Lorenzo O, Rupérez M, et al.: Angiotensin II activates nuclear transcription factor-kB in aorta of normal rats and in vascular smooth muscle cells of AT1 knockout mice. Nephrol Dial Transplant 2001, 16(Suppl 6):1–7

    Google Scholar 

  49. Ruiz-Ortega M, Lorenzo O, Egido J: Angiotensin III increases MCP-1 and activates NF-kappaB and AP-1 in cultured mesangial and mononuclear cells. Kidney Int 2000, 57:2285–2298.

    Article  PubMed  CAS  Google Scholar 

  50. Lorenzo O, Ruiz-Ortega M, Suzuki Y, et al.: Angiotensin III activates nuclear transcription factor-kb in cultured mesangial cells mainly via AT2 receptors: studies with AT1 receptorknockout mice. J Am Soc Nephrol 2002, 13:1162–1171.

    Article  PubMed  CAS  Google Scholar 

  51. Wolf G, Ziyadeh FN, Thaiss F, et al.: Angiontensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor. J Clin Invest 1997, 100:1047–1058.

    PubMed  CAS  Google Scholar 

  52. Akishita M, Horiuchi M, Yamada H, et al.: Inflammation influences vascular remodeling through AT2 receptor expression and signaling. Physiol Genomics 2000, 24:13–20. This paper examines the in vivo role of the AT2 receptor in vascular diseases, and shows that this receptor plays an important role in nonocclusive inflammatory injury by mediating the effects of inflammation on vascular smooth muscle growth inhibition.

    Google Scholar 

  53. Li JY, Avallet O, Berthelon MC, et al.: Transcriptional and translational regulation of angiotensin II type 2 receptor by angiotensin II and growth factors. Endocrinology 1999, 140:4988–4994.

    Article  PubMed  CAS  Google Scholar 

  54. Senbonmatsu T, Ichihara S, Price E Jr, et al.: Evidence for angiotensin II type 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload. J Clin Invest 2000, 106:R25-R29.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ruiz-Ortega, M., Ruperez, M., Esteban, V. et al. Molecular mechanisms of angiotensin II-induced vascular injury. Current Science Inc 5, 73–79 (2003). https://doi.org/10.1007/s11906-003-0014-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-003-0014-0

Keywords

Navigation