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. 1995 Jul;96(1):141–149. doi: 10.1172/JCI118014

Nitric oxide inhibits angiotensin II-induced migration of rat aortic smooth muscle cell. Role of cyclic-nucleotides and angiotensin1 receptors.

R K Dubey 1, E K Jackson 1, T F Lüscher 1
PMCID: PMC185182  PMID: 7615784

Abstract

Nitric oxide (NO) and angiotensin II (AII) can effect vascular smooth muscle cell (SMC) proliferation. However, the effects of such agents on SMC migration, an equally important phenomenon with regard to vascular pathophysiology, have received little attention. The objectives of the present study were: (a) to determine whether NO inhibits AII-induced migration of vascular SMCs; (b) to investigate the mechanism of the interaction of NO and AII on SMC migration; and (c) to evaluate the AII receptor subtype that mediates AII-induced SMC migration. Migration of rat SMCs was evaluated using a modified Boydens Chamber (transwell inserts with gelatin-coated polycarbonate membranes, 8 microns pore size). AII stimulated SMC migration in a concentration-dependent manner, and this effect was inhibited by sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP). In the presence of L-arginine, but not D-arginine, IL-1 beta, an inducer of inducible NO synthase, also inhibited AII-induced SMC migration, and this effect was prevented by the NO-synthase inhibitor, N-nitro-L-arginine methyl ester. The effects of NO donors on AII-induced SMC migration were mimicked by 8-bromo-cGMP. Also, the antimigratory effects of SNAP were partially inhibited by LY83583 (an inhibitor of soluble guanylyl cyclase) and by KT5823 (an inhibitor of cGMP-dependent protein kinase). Although 8-bromo-cAMP (cAMP) also mimicked the antimigratory effects of NO donors, the antimigratory effects of SNAP were not altered by 2',5'-dideoxyadenosine (an inhibitor of adenyl cyclase) or by (R)-p-adenosine-3',5'-cyclic phosphorothioate (an inhibitor of the cAMP-dependent protein kinase). Low concentrations of the subtype AT1-receptor antagonist CGP 48933, but not the subtype AT2-receptor antagonist CGP 42112, blocked AII-induced SMC migration. These findings indicate that (a) NO inhibits AII-induced migration of vascular SMCs; (b) the antimigratory effect of NO is mediated in part via a cGMP-dependent mechanism; and (c) AII stimulates SMC migration via an AT1 receptor.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Admiraal P. J., Danser A. H., Derkx F. H., Schalekamp M. A. Angiotensin II production in different vascular beds in hypertensive subjects. J Hypertens Suppl. 1991 Dec;9(6):S208–S209. [PubMed] [Google Scholar]
  2. Beasley D., Schwartz J. H., Brenner B. M. Interleukin 1 induces prolonged L-arginine-dependent cyclic guanosine monophosphate and nitrite production in rat vascular smooth muscle cells. J Clin Invest. 1991 Feb;87(2):602–608. doi: 10.1172/JCI115036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bell L., Madri J. A. Effect of platelet factors on migration of cultured bovine aortic endothelial and smooth muscle cells. Circ Res. 1989 Oct;65(4):1057–1065. doi: 10.1161/01.res.65.4.1057. [DOI] [PubMed] [Google Scholar]
  4. Bell L., Madri J. A. Influence of the angiotensin system on endothelial and smooth muscle cell migration. Am J Pathol. 1990 Jul;137(1):7–12. [PMC free article] [PubMed] [Google Scholar]
  5. Bunkenburg B., van Amelsvoort T., Rogg H., Wood J. M. Receptor-mediated effects of angiotensin II on growth of vascular smooth muscle cells from spontaneously hypertensive rats. Hypertension. 1992 Dec;20(6):746–754. doi: 10.1161/01.hyp.20.6.746. [DOI] [PubMed] [Google Scholar]
  6. Campbell J. H., Campbell G. R. Endothelial cell influences on vascular smooth muscle phenotype. Annu Rev Physiol. 1986;48:295–306. doi: 10.1146/annurev.ph.48.030186.001455. [DOI] [PubMed] [Google Scholar]
  7. Casscells W. Migration of smooth muscle and endothelial cells. Critical events in restenosis. Circulation. 1992 Sep;86(3):723–729. doi: 10.1161/01.cir.86.3.723. [DOI] [PubMed] [Google Scholar]
  8. Clowes A. W., Reidy M. A., Clowes M. M. Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. Lab Invest. 1983 Sep;49(3):327–333. [PubMed] [Google Scholar]
  9. Clowes A. W., Schwartz S. M. Significance of quiescent smooth muscle migration in the injured rat carotid artery. Circ Res. 1985 Jan;56(1):139–145. doi: 10.1161/01.res.56.1.139. [DOI] [PubMed] [Google Scholar]
  10. Criscione L., de Gasparo M., Bühlmayer P., Whitebread S., Ramjoué H. P., Wood J. Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype. Br J Pharmacol. 1993 Oct;110(2):761–771. doi: 10.1111/j.1476-5381.1993.tb13877.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. De Mey J. G., Dijkstra E. H., Vrijdag M. J. Endothelium reduces DNA synthesis in isolated arteries. Am J Physiol. 1991 Apr;260(4 Pt 2):H1128–H1134. doi: 10.1152/ajpheart.1991.260.4.H1128. [DOI] [PubMed] [Google Scholar]
  12. Dinerman J. L., Lowenstein C. J., Snyder S. H. Molecular mechanisms of nitric oxide regulation. Potential relevance to cardiovascular disease. Circ Res. 1993 Aug;73(2):217–222. doi: 10.1161/01.res.73.2.217. [DOI] [PubMed] [Google Scholar]
  13. Dubey R. K., Overbeck H. W. Culture of rat mesenteric arteriolar smooth muscle cells: effects of platelet-derived growth factor, angiotensin, and nitric oxide on growth. Cell Tissue Res. 1994 Jan;275(1):133–141. doi: 10.1007/BF00305381. [DOI] [PubMed] [Google Scholar]
  14. Dubey R. K., Roy A., Overbeck H. W. Culture of renal arteriolar smooth muscle cells. Mitogenic responses to angiotensin II. Circ Res. 1992 Nov;71(5):1143–1152. doi: 10.1161/01.res.71.5.1143. [DOI] [PubMed] [Google Scholar]
  15. Dubey R. K. Vasodilator-derived nitric oxide inhibits fetal calf serum- and angiotensin-II-induced growth of renal arteriolar smooth muscle cells. J Pharmacol Exp Ther. 1994 Apr;269(1):402–408. [PubMed] [Google Scholar]
  16. Dzau V. J., Gibbons G. H. Vascular remodeling: mechanisms and implications. J Cardiovasc Pharmacol. 1993;21 (Suppl 1):S1–S5. [PubMed] [Google Scholar]
  17. Fiscus R. R., Hao H., Wang X., Arden W. A., Diana J. N. Nitroglycerin (exogenous nitric oxide) substitutes for endothelium-derived nitric oxide in potentiating vasorelaxations and cyclic AMP elevations induced by calcitonin gene-related peptide (CGRP) in rat aorta. Neuropeptides. 1994 Feb;26(2):133–144. doi: 10.1016/0143-4179(94)90104-x. [DOI] [PubMed] [Google Scholar]
  18. Flavahan N. A. Atherosclerosis or lipoprotein-induced endothelial dysfunction. Potential mechanisms underlying reduction in EDRF/nitric oxide activity. Circulation. 1992 May;85(5):1927–1938. doi: 10.1161/01.cir.85.5.1927. [DOI] [PubMed] [Google Scholar]
  19. Fukumoto Y., Kawahara Y., Kariya K., Araki S., Fukuzaki H., Takai Y. Independent inhibition of DNA synthesis by protein kinase C, cyclic AMP and interferon alpha/beta in rabbit aortic smooth muscle cells. Biochem Biophys Res Commun. 1988 Nov 30;157(1):337–345. doi: 10.1016/s0006-291x(88)80052-4. [DOI] [PubMed] [Google Scholar]
  20. Furchgott R. F., Zawadzki J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373–376. doi: 10.1038/288373a0. [DOI] [PubMed] [Google Scholar]
  21. Garg U. C., Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989 May;83(5):1774–1777. doi: 10.1172/JCI114081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gibbons G. H. Autocrine-paracrine factors and vascular remodeling in hypertension. Curr Opin Nephrol Hypertens. 1993 Mar;2(2):291–298. doi: 10.1097/00041552-199303000-00017. [DOI] [PubMed] [Google Scholar]
  23. Grotendorst G. R., Seppä H. E., Kleinman H. K., Martin G. R. Attachment of smooth muscle cells to collagen and their migration toward platelet-derived growth factor. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3669–3672. doi: 10.1073/pnas.78.6.3669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Haslam R. J., Davidson M. M., Desjardins J. V. Inhibition of adenylate cyclase by adenosine analogues in preparations of broken and intact human platelets. Evidence for the unidirectional control of platelet function by cyclic AMP. Biochem J. 1978 Oct 15;176(1):83–95. doi: 10.1042/bj1760083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Heagerty A. M., Aalkjaer C., Bund S. J., Korsgaard N., Mulvany M. J. Small artery structure in hypertension. Dual processes of remodeling and growth. Hypertension. 1993 Apr;21(4):391–397. doi: 10.1161/01.hyp.21.4.391. [DOI] [PubMed] [Google Scholar]
  26. Ignarro L. J., Lippton H., Edwards J. C., Baricos W. H., Hyman A. L., Kadowitz P. J., Gruetter C. A. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther. 1981 Sep;218(3):739–749. [PubMed] [Google Scholar]
  27. Jackson C. L., Schwartz S. M. Pharmacology of smooth muscle cell replication. Hypertension. 1992 Dec;20(6):713–736. doi: 10.1161/01.hyp.20.6.713. [DOI] [PubMed] [Google Scholar]
  28. Janiak P., Pillon A., Prost J. F., Vilaine J. P. Role of angiotensin subtype 2 receptor in neointima formation after vascular injury. Hypertension. 1992 Dec;20(6):737–745. doi: 10.1161/01.hyp.20.6.737. [DOI] [PubMed] [Google Scholar]
  29. Joly G. A., Schini V. B., Vanhoutte P. M. Balloon injury and interleukin-1 beta induce nitric oxide synthase activity in rat carotid arteries. Circ Res. 1992 Aug;71(2):331–338. doi: 10.1161/01.res.71.2.331. [DOI] [PubMed] [Google Scholar]
  30. Kase H., Iwahashi K., Nakanishi S., Matsuda Y., Yamada K., Takahashi M., Murakata C., Sato A., Kaneko M. K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. Biochem Biophys Res Commun. 1987 Jan 30;142(2):436–440. doi: 10.1016/0006-291x(87)90293-2. [DOI] [PubMed] [Google Scholar]
  31. Koyama N., Morisaki N., Saito Y., Yoshida S. Regulatory effects of platelet-derived growth factor-AA homodimer on migration of vascular smooth muscle cells. J Biol Chem. 1992 Nov 15;267(32):22806–22812. [PubMed] [Google Scholar]
  32. Martin W., Villani G. M., Jothianandan D., Furchgott R. F. Selective blockade of endothelium-dependent and glyceryl trinitrate-induced relaxation by hemoglobin and by methylene blue in the rabbit aorta. J Pharmacol Exp Ther. 1985 Mar;232(3):708–716. [PubMed] [Google Scholar]
  33. Maurice D. H., Haslam R. J. Molecular basis of the synergistic inhibition of platelet function by nitrovasodilators and activators of adenylate cyclase: inhibition of cyclic AMP breakdown by cyclic GMP. Mol Pharmacol. 1990 May;37(5):671–681. [PubMed] [Google Scholar]
  34. Moncada S., Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993 Dec 30;329(27):2002–2012. doi: 10.1056/NEJM199312303292706. [DOI] [PubMed] [Google Scholar]
  35. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  36. Muir D., Sukhu L., Johnson J., Lahorra M. A., Maria B. L. Quantitative methods for scoring cell migration and invasion in filter-based assays. Anal Biochem. 1993 Nov 15;215(1):104–109. doi: 10.1006/abio.1993.1561. [DOI] [PubMed] [Google Scholar]
  37. Mülsch A., Busse R., Liebau S., Förstermann U. LY 83583 interferes with the release of endothelium-derived relaxing factor and inhibits soluble guanylate cyclase. J Pharmacol Exp Ther. 1988 Oct;247(1):283–288. [PubMed] [Google Scholar]
  38. Nakayama D. K., Geller D. A., Lowenstein C. J., Chern H. D., Davies P., Pitt B. R., Simmons R. L., Billiar T. R. Cytokines and lipopolysaccharide induce nitric oxide synthase in cultured rat pulmonary artery smooth muscle. Am J Respir Cell Mol Biol. 1992 Nov;7(5):471–476. doi: 10.1165/ajrcmb/7.5.471. [DOI] [PubMed] [Google Scholar]
  39. Palmer R. M., Ashton D. S., Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988 Jun 16;333(6174):664–666. doi: 10.1038/333664a0. [DOI] [PubMed] [Google Scholar]
  40. Panza J. A., Quyyumi A. A., Brush J. E., Jr, Epstein S. E. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med. 1990 Jul 5;323(1):22–27. doi: 10.1056/NEJM199007053230105. [DOI] [PubMed] [Google Scholar]
  41. Prescott M. F., Webb R. L., Reidy M. A. Angiotensin-converting enzyme inhibitor versus angiotensin II, AT1 receptor antagonist. Effects on smooth muscle cell migration and proliferation after balloon catheter injury. Am J Pathol. 1991 Dec;139(6):1291–1296. [PMC free article] [PubMed] [Google Scholar]
  42. Rapoport R. M., Draznin M. B., Murad F. Endothelium-dependent vasodilator-and nitrovasodilator-induced relaxation may be mediated through cyclic GMP formation and cyclic GMP-dependent protein phosphorylation. Trans Assoc Am Physicians. 1983;96:19–30. [PubMed] [Google Scholar]
  43. Ross R. The smooth muscle cell. II. Growth of smooth muscle in culture and formation of elastic fibers. J Cell Biol. 1971 Jul;50(1):172–186. doi: 10.1083/jcb.50.1.172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Rothermel J. D., Parker Botelho L. H. A mechanistic and kinetic analysis of the interactions of the diastereoisomers of adenosine 3',5'-(cyclic)phosphorothioate with purified cyclic AMP-dependent protein kinase. Biochem J. 1988 May 1;251(3):757–762. doi: 10.1042/bj2510757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Rubanyi G. M., Vanhoutte P. M. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol. 1986 May;250(5 Pt 2):H822–H827. doi: 10.1152/ajpheart.1986.250.5.H822. [DOI] [PubMed] [Google Scholar]
  46. Scott-Burden T., Elizondo E., Ge T., Boulanger C. M., Vanhoutte P. M. Simultaneous activation of adenylyl cyclase and protein kinase C induces production of nitric oxide by vascular smooth muscle cells. Mol Pharmacol. 1994 Aug;46(2):274–282. [PubMed] [Google Scholar]
  47. Scott-Burden T., Schini V. B., Elizondo E., Junquero D. C., Vanhoutte P. M. Platelet-derived growth factor suppresses and fibroblast growth factor enhances cytokine-induced production of nitric oxide by cultured smooth muscle cells. Effects on cell proliferation. Circ Res. 1992 Nov;71(5):1088–1100. doi: 10.1161/01.res.71.5.1088. [DOI] [PubMed] [Google Scholar]
  48. Timmermans P. B., Benfield P., Chiu A. T., Herblin W. F., Wong P. C., Smith R. D. Angiotensin II receptors and functional correlates. Am J Hypertens. 1992 Dec;5(12 Pt 2):221S–235S. doi: 10.1093/ajh/5.12.221s. [DOI] [PubMed] [Google Scholar]
  49. Yang Z. H., von Segesser L., Bauer E., Stulz P., Turina M., Lüscher T. F. Different activation of the endothelial L-arginine and cyclooxygenase pathway in the human internal mammary artery and saphenous vein. Circ Res. 1991 Jan;68(1):52–60. doi: 10.1161/01.res.68.1.52. [DOI] [PubMed] [Google Scholar]
  50. van Kleef E. M., Smits J. F., De Mey J. G., Cleutjens J. P., Lombardi D. M., Schwartz S. M., Daemen M. J. Alpha 1-adrenoreceptor blockade reduces the angiotensin II-induced vascular smooth muscle cell DNA synthesis in the rat thoracic aorta and carotid artery. Circ Res. 1992 Jun;70(6):1122–1127. doi: 10.1161/01.res.70.6.1122. [DOI] [PubMed] [Google Scholar]

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