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Angiotensin-(1–7) Modulates Angiotensin II-Induced Vasoconstriction in Human Mammary Artery

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Abstract

Purpose

The renin-angiotensin system plays a key role in cardiovascular pathophysiology and one of its members, angiotensin-(1–7) (ANG-(1–7)), is now recognized as a peptide with the ability to counter-regulate angiotensin II (ANGII) effects. We sought to investigate ANG-(1–7) actions in human vessels, particularly its effect on ANGII-induced vasoconstriction in human mammary arteries (HMA).

Methods

Samples of HMA from patients submitted to coronary revascularization (22 patients, mean age 67 years) were cut into small rings, mounted in a myograph bath system, normalized and allowed to contract and dilate isometrically. In baseline experiments, the rings were incubated with ANG-(1–7) or vehicle, followed by increasing concentrations of ANGII. This protocol was repeated in the presence of A-779, PD123177, losartan and after mechanical endothelium removal. Western blot analysis and immunofluorescence were also performed in order to verify the presence of Mas receptor in HMA.

Results

ANG-(1–7) significantly attenuated ANGII-induced contraction, producing a maximal inhibition of approximately 65.2 %. This effect was not abolished by A-779, PD123177 or endothelium removal. In the presence of losartan, ANGII response was attenuated and no differences were observed between ANG-(1–7) and vehicle treated rings. Finally, we observed, for the first time, that the Mas receptor is expressed in HMA endothelium.

Conclusions

ANG-(1–7) significantly attenuates ANGII-induced vasoconstriction and, although the Mas receptor is expressed in HMA, this effect seems to be independent of its activation. Additionally, AT2 receptor and endothelium are not involved in this mechanism, which suggests a direct effect on smooth muscle cells.

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References

  1. Castro-Chaves P, Cerqueira R, Pintalhao M, Leite-Moreira AF. New pathways of the renin-angiotensin system: the role of ACE2 in cardiovascular pathophysiology and therapy. Expert Opin Ther Targets. 2010;14(5):485–96.

    Article  CAS  PubMed  Google Scholar 

  2. Genest J. Angiotensin, aldosterone and human arterial hypertension. Can Med Assoc J. 1961;84:403–19.

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Carey RM. Newly discovered components and actions of the renin-angiotensin system. Hypertension. 2013;62(5):818–22.

    Article  CAS  PubMed  Google Scholar 

  4. Iwai M, Horiuchi M. Devil and angel in the renin-angiotensin system: ACE-angiotensin II-AT1 receptor axis vs. ACE2-angiotensin-(1–7)-Mas receptor axis. Hypertens Res. 2009;32(7):533–6.

    Article  CAS  PubMed  Google Scholar 

  5. Strawn WB, Ferrario CM, Tallant EA. Angiotensin-(1–7) reduces smooth muscle growth after vascular injury. Hypertension. 1999;33(1 Pt 2):207–11.

    Article  CAS  PubMed  Google Scholar 

  6. Wang L, Hu X, Zhang W, Tian F. Angiotensin (1–7) ameliorates angiotensin II-induced inflammation by inhibiting LOX-1 expression. Inflamm Res. 2013;62(2):219–28.

    Article  CAS  PubMed  Google Scholar 

  7. Wang Y, Tikellis C, Thomas MC, Golledge J. Angiotensin converting enzyme 2 and atherosclerosis. Atherosclerosis. 2013;226(1):3–8.

    Article  CAS  PubMed  Google Scholar 

  8. Jawien J, Toton-Zuranska J, Gajda M, Niepsuj A, Gebska A, Kus K, et al. Angiotensin-(1–7) receptor Mas agonist ameliorates progress of atherosclerosis in apoE-knockout mice. J Physiol Pharmacol. 2012;63(1):77–85.

    CAS  PubMed  Google Scholar 

  9. Brosnihan KB, Li P, Ferrario CM. Angiotensin-(1–7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension. 1996;27(3 Pt 2):523–8.

    Article  CAS  PubMed  Google Scholar 

  10. Gorelik G, Carbini LA, Scicli AG. Angiotensin 1–7 induces bradykinin-mediated relaxation in porcine coronary artery. J Pharmacol Exp Ther. 1998;286(1):403–10.

    CAS  PubMed  Google Scholar 

  11. Brosnihan KB, Li P, Tallant EA, Ferrario CM. Angiotensin-(1–7): a novel vasodilator of the coronary circulation. Biol Res. 1998;31(3):227–34.

    CAS  PubMed  Google Scholar 

  12. Santos RA, Silva e Simoes AC, Maric C, Silva DM, Machado RP, de Buhr I, et al. Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A. 2003;100(14):8258–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Santos RA, Ferreira AJ. Angiotensin-(1–7) and the renin-angiotensin system. Curr Opin Nephrol Hypertens. 2007;16(2):122–8.

    Article  CAS  PubMed  Google Scholar 

  14. Peiro C, Vallejo S, Gembardt F, Azcutia V, Heringer-Walther S, Rodriguez-Manas L, et al. Endothelial dysfunction through genetic deletion or inhibition of the G protein-coupled receptor Mas: a new target to improve endothelial function. J Hypertens. 2007;25(12):2421–5.

    Article  CAS  PubMed  Google Scholar 

  15. Sampaio WO, Santos dos Souza RA, Faria-Silva R, da Mata Machado LT, Schiffrin EL, Touyz RM. Angiotensin-(1–7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension. 2007;49(1):185–92.

    Article  CAS  PubMed  Google Scholar 

  16. Chen Z, Tang Y, Yang Z, Liu S, Liu Y, Li Y, et al. Endothelin-1 downregulates Mas receptor expression in human cardiomyocytes. Mol Med. 2013;8(3):871–6.

    CAS  Google Scholar 

  17. Bernardi S, Zennaro C, Palmisano S, Velkoska E, Sabato N, Toffoli B, et al. Characterization and significance of ACE2 and Mas receptor in human colon adenocarcinoma. J Renin-Angiotensin-Aldosterone Syst. 2012;13(1):202–9.

    Article  CAS  PubMed  Google Scholar 

  18. Reis AB, Araujo FC, Pereira VM, Dos Reis AM, Santos RA, Reis FM. Angiotensin (1–7) and its receptor Mas are expressed in the human testis: implications for male infertility. J Mol Histol. 2010;41(1):75–80.

    Article  CAS  PubMed  Google Scholar 

  19. Santos RA. Angiotensin-(1–7). Hypertension. 2014;63(6):1138–47.

    Article  CAS  PubMed  Google Scholar 

  20. Castro CH, Santos RA, Ferreira AJ, Bader M, Alenina N, Almeida AP. Evidence for a functional interaction of the angiotensin-(1–7) receptor Mas with AT1 and AT2 receptors in the mouse heart. Hypertension. 2005;46(4):937–42.

    Article  PubMed  Google Scholar 

  21. Souza AP, Sobrinho DB, Almeida JF, Alves GM, Macedo LM, Porto JE, et al. Angiotensin II type 1 receptor blockade restores angiotensin-(1–7)-induced coronary vasodilation in hypertrophic rat hearts. Clin Sci (Lond). 2013;125(9):449–59.

    Article  CAS  Google Scholar 

  22. van de Wal RM, van der Harst P, Wagenaar LJ, Wassmann S, Morshuis WJ, Nickenig G, et al. Angiotensin II type 2 receptor vasoactivity in internal mammary arteries of patients with coronary artery disease. J Cardiovasc Pharmacol. 2007;50(4):372–9.

    Article  PubMed  Google Scholar 

  23. Clark MA, Diz DI, Tallant EA. Angiotensin-(1–7) downregulates the angiotensin II type 1 receptor in vascular smooth muscle cells. Hypertension. 2001;37(4):1141–6.

    Article  CAS  PubMed  Google Scholar 

  24. Ueda S, Masumori-Maemoto S, Ashino K, Nagahara T, Gotoh E, Umemura S, et al. Angiotensin-(1–7) attenuates vasoconstriction evoked by angiotensin II but not by noradrenaline in man. Hypertension. 2000;35(4):998–1001.

    Article  CAS  PubMed  Google Scholar 

  25. Roks AJ, van Geel PP, Pinto YM, Buikema H, Henning RH, de Zeeuw D, et al. Angiotensin-(1–7) is a modulator of the human renin-angiotensin system. Hypertension. 1999;34(2):296–301.

    Article  CAS  PubMed  Google Scholar 

  26. Grapow MT, Reineke DC, Kern T, Muller-Schweinitzer E, Carrel T, Eckstein FS. Human internal thoracic arteries from diabetic patients are resistant to endothelial dysfunction. Fundam Clin Pharmacol. 2009;23(5):567–72.

    Article  CAS  PubMed  Google Scholar 

  27. Nikkari ST, Sisto T, Nikkari T. Ultrastructural, immunochemical and electrophoretic study of smooth muscle cells in internal mammary arteries of patients undergoing coronary bypass surgery. Atherosclerosis. 1989;79(2–3):129–38.

    Article  CAS  PubMed  Google Scholar 

  28. Zulli A, Hare DL, Horrigan M, Buxton BF. The resistance of the IMA to atherosclerosis might be associated with its higher eNOS, ACE and ET-A receptor immunoreactivity. Arterioscler Thromb Vasc Biol. 2003;23(7):1308.

    Article  CAS  PubMed  Google Scholar 

  29. Buikema H, Grandjean JG, van den Broek S, van Gilst WH, Lie KI, Wesseling H. Differences in vasomotor control between human gastroepiploic and left internal mammary artery. Circulation. 1992;86(5 Suppl):II205–9.

    CAS  PubMed  Google Scholar 

  30. Martinez-Revelles S, Jimenez-Altayo F, Caracuel L, Perez-Asensio FJ, Planas AM, Vila E. Endothelial dysfunction in rat mesenteric resistance artery after transient middle cerebral artery occlusion. J Pharmacol Exp Ther. 2008;325(2):363–9.

    Article  CAS  PubMed  Google Scholar 

  31. Mugge A, Barton MR, Cremer J, Frombach R, Lichtlen PR. Different vascular reactivity of human internal mammary and inferior epigastric arteries in vitro. Ann Thorac Surg. 1993;56(5):1085–9.

    Article  CAS  PubMed  Google Scholar 

  32. Filho AG, Ferreira AJ, Santos SH, Neves SR, Silva Camargos ER, Becker LK, et al. Selective increase of angiotensin (1–7) and its receptor in hearts of spontaneously hypertensive rats subjected to physical training. Exp Physiol. 2008;93(5):589–98.

    Article  PubMed  Google Scholar 

  33. Silva DM, Gomes-Filho A, Olivon VC, Santos TM, Becker LK, Santos RA, et al. Swimming training improves the vasodilator effect of angiotensin-(1–7) in the aorta of spontaneously hypertensive rat. J Appl Physiol. 2011;111(5):1272–7.

    Article  CAS  PubMed  Google Scholar 

  34. Nematbakhsh M, Safari T. Role of Mas receptor in renal blood flow response to angiotensin (1–7) in male and female rats. General physiology and biophysics. 2014.

  35. Raffai G, Durand MJ, Lombard JH. Acute and chronic angiotensin-(1–7) restores vasodilation and reduces oxidative stress in mesenteric arteries of salt-fed rats. Am J Physiol Heart Circ Physiol. 2011;301(4):H1341–52.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Durand MJ, Raffai G, Weinberg BD, Lombard JH. Angiotensin-(1–7) and low-dose angiotensin II infusion reverse salt-induced endothelial dysfunction via different mechanisms in rat middle cerebral arteries. Am J Physiol Heart Circ Physiol. 2010;299(4):H1024–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Benter IF, Ferrario CM, Morris M, Diz DI. Antihypertensive actions of angiotensin-(1–7) in spontaneously hypertensive rats. Am J Physiol. 1995;269(1 Pt 2):H313–9.

    CAS  PubMed  Google Scholar 

  38. Stegbauer J, Oberhauser V, Vonend O, Rump LC. Angiotensin-(1–7) modulates vascular resistance and sympathetic neurotransmission in kidneys of spontaneously hypertensive rats. Cardiovasc Res. 2004;61(2):352–9.

    Article  CAS  PubMed  Google Scholar 

  39. Ferrario CM. Angiotension-(1–7) and antihypertensive mechanisms. Am J Nephrol. 1998;11(6):278–83.

    CAS  Google Scholar 

  40. Dora KA, Garland CJ. Properties of smooth muscle hyperpolarization and relaxation to K + in the rat isolated mesenteric artery. Am J Physiol Heart Circ Physiol. 2001;280(6):H2424–9.

    CAS  PubMed  Google Scholar 

  41. Lemos VS, Silva DM, Walther T, Alenina N, Bader M, Santos RA. The endothelium-dependent vasodilator effect of the nonpeptide Ang (1–7) mimic AVE 0991 is abolished in the aorta of mas-knockout mice. J Cardiovasc Pharmacol. 2005;46(3):274–9.

    Article  CAS  PubMed  Google Scholar 

  42. Santos RA, Ferreira AJ. Pharmacological effects of AVE 0991, a nonpeptide angiotensin-(1–7) receptor agonist. Cardiovasc Drug Rev. 2006;24(3–4):239–46.

    Article  CAS  PubMed  Google Scholar 

  43. Gembardt F, Grajewski S, Vahl M, Schultheiss HP, Walther T. Angiotensin metabolites can stimulate receptors of the Mas-related genes family. Mol Cell Biochem. 2008;319(1–2):115–23.

    Article  CAS  PubMed  Google Scholar 

  44. Lautner RQ, Villela DC, Fraga-Silva RA, Silva N, Verano-Braga T, Costa-Fraga F, et al. Discovery and characterization of alamandine: a novel component of the renin-angiotensin system. Circ Res. 2013;112(8):1104–11.

    Article  CAS  PubMed  Google Scholar 

  45. Silva DM, Vianna HR, Cortes SF, Campagnole-Santos MJ, Santos RA, Lemos VS. Evidence for a new angiotensin-(1–7) receptor subtype in the aorta of Sprague–Dawley rats. Peptides. 2007;28(3):702–7.

    Article  CAS  PubMed  Google Scholar 

  46. Herath CB, Mak K, Burrell LM, Angus PW. Angiotensin-(1–7) reduces the portal pressure response to angiotensin II and methoxamine via an endothelial nitric oxide mediated pathway in cirrhotic rat liver. Am J Physiol Gastrointest Liver Physiol. 2012.

  47. Hollenberg NK. Implications of species difference for clinical investigation: studies on the renin-angiotensin system. Hypertension. 2000;35(1 Pt 2):150–4.

    Article  CAS  PubMed  Google Scholar 

  48. Hollenberg NK, Passan DR. Specificity of renal vasodilation with captopril: saralasin prevents the response in the DOCA-treated, salt-loaded rabbit. Life Sci. 1982;31(4):329–34.

    Article  CAS  PubMed  Google Scholar 

  49. Nakagawa M, Stewart JM, Vavrek RJ, Nasjletti A. Effects of a kinin antagonist on renal function in rats. Am J Physiol. 1990;258(3 Pt 2):F643–8.

    CAS  PubMed  Google Scholar 

  50. Mahon JM, Carr RD, Nicol AK, Henderson IW. Angiotensin (1–7) is an antagonist at the type 1 angiotensin II receptor. J Hypertens. 1994;12(12):1377–81.

    Article  CAS  PubMed  Google Scholar 

  51. Sampaio WO, Nascimento AA, Santos RA. Systemic and regional hemodynamic effects of angiotensin-(1–7) in rats. Am J Physiol Heart Circ Physiol. 2003;284(6):H1985–94.

    CAS  PubMed  Google Scholar 

  52. Unger T, Chung O, Csikos T, Culman J, Gallinat S, Gohlke P, et al. Angiotensin receptors. J Hypertens Suppl. 1996;14(5):S95–103.

    CAS  PubMed  Google Scholar 

  53. Graham RM, Perez DM, Hwa J, Piascik MT. Alpha 1-adrenergic receptor subtypes. Molecular structure, function, and signaling. Circ Res. 1996;78(5):737–49.

    Article  CAS  PubMed  Google Scholar 

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Disclosures

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal

    Luís Mendonça, Pedro Mendes-Ferreira, Ana Bento-Leite, Rui Cerqueira, Mário Jorge Amorim, Paulo Pinho, Cármen Brás-Silva, Adelino F. Leite-Moreira & Paulo Castro-Chaves

  2. Department of Cardiothoracic Surgery, Centro Hospitalar S. João, Porto, Portugal

    Rui Cerqueira, Mário Jorge Amorim, Paulo Pinho & Adelino F. Leite-Moreira

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  1. Luís Mendonça
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  2. Pedro Mendes-Ferreira
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Correspondence to Paulo Castro-Chaves.

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Mendonça, L., Mendes-Ferreira, P., Bento-Leite, A. et al. Angiotensin-(1–7) Modulates Angiotensin II-Induced Vasoconstriction in Human Mammary Artery. Cardiovasc Drugs Ther 28, 513–522 (2014). https://doi.org/10.1007/s10557-014-6555-4

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