Journal of Hepatology
Volume 50, Issue 2 , Pages 296-305 , February 2009

Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension

Received 11 August 2008 ,Revised 19 September 2008 ,Accepted 23 September 2008.

References 

  1. Bosch J, Pizcueta P, Feu F, Fernandez M, Garcia-Pagan JC. Pathophysiology of portal hypertension. Gastroenterol Clin North Am. 1992;21:1–13
  2. Folkman J, D’Amore PA. Blood vessel formation: what is its molecular basis?. Cell. 1996;87:1153–1155
  3. Risau W. Mechanisms of angiogenesis. Nature. 1997;386:671–674
  4. Fernandez M, Vizzutti F, Garcia-Pagan JC, Rodes J, Bosch J. Anti-VEGF receptor-2 monoclonal antibody prevents portal–systemic collateral vessel formation in portal hypertensive mice. Gastroenterology. 2004;126:886–894
  5. Fernandez M, Mejias M, Angermayr B, Garcia-Pagan JC, Rodes J, Bosch J. Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal–systemic collateral vessels in portal hypertensive rats. J Hepatol. 2005;43:98–103
  6. Angermayr B, Mejias M, Gracia-Sancho J, Garcia-Pagan JC, Bosch J, Fernandez M. Heme oxygenase attenuates oxidative stress and inflammation, and increases VEGF expression in portal hypertensive rats. J Hepatol. 2006;44:1033–1039
  7. Angermayr B, Fernandez M, Mejias M, Gracia-Sancho J, Garcia-Pagan JC, Bosch J. NAD(P)H oxidase modulates angiogenesis and the development of portosystemic collaterals and splanchnic hyperemia in portal hypertensive rats. Gut. 2007;56:560–564
  8. Fernandez M, Mejias M, Garcia-Pras E, Mendez R, Garcia-Pagan JC, Bosch J. Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats. Hepatology. 2007;46:1208–1217
  9. Mejias M, Garcia-Pras E, Tiani C, Bosch J, Fernandez M. The somatostatin analogue octreotide inhibits angiogenesis in the earliest, but not in advanced, stages of portal hypertension in rats. J Cell Mol Med. 2008;12:1690–1699
  10. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–676
  11. Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997;277:242–245
  12. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8:299–309
  13. Masri B, Knibiehler B, Audigier Y. Apelin signalling: a promising pathway from cloning to pharmacology. Cell Signal. 2005;17:415–426
  14. Devic E, Rizzoti K, Bodin S, Knibiehler B, Audigier Y. Amino acid sequence and embryonic expression of msr/apj, the mouse homolog of Xenopus X-msr and human APJ. Mech Dev. 1999;84:199–203
  15. Cox CM, D’Agostino SL, Miller MK, Heimark RL, Krieg PA. Apelin, the ligand for the endothelial G-protein-coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo. Dev Biol. 2006;296:177–189
  16. Inui M, Fukui A, Ito Y, Asashima M. Xapelin and Xmsr are required for cardiovascular development in Xenopus laevis. Dev Biol. 2006;298:188–200
  17. Saint-Geniez M, Masri B, Malecaze F, Knibiehler B, Audigier Y. Expression of the murine msr/apj receptor and its ligand apelin is upregulated during formation of the retinal vessels. Mech Dev. 2002;110:183–186
  18. Saint-Geniez M, Argence CB, Knibiehler B, Audigier Y. The msr/apj gene encoding the apelin receptor is an early and specific marker of the venous phenotype in the retinal vasculature. Gene Expr Patterns. 2003;3:467–472
  19. Kasai A, Shintani N, Oda M, Kakuda M, Hashimoto H, Matsuda T, et al. Apelin is a novel angiogenic factor in retinal endothelial cells. Biochim Biophys Res Commun. 2004;325:395–400
  20. Kasai A, Shintani N, Kato H, Matsuda S, Gomi F, Haba R, et al. Retardation of retinal vascular development in apelin-deficient mice. Arterioscler Thromb Vasc Biol. 2008;28:1717–1722
  21. Masri B, Morin N, Cornu M, Knibiehler B, Audigier Y. Apelin (65–77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells. FASEB J. 2004;18:1909–1911
  22. Kidoya H, Ueno M, Yamada Y, Mochizuki N, Nakata M, Yano T, et al. Spatial and temporal role of the apelin/APJ system in the caliber size regulation of blood vessels during angiogenesis. EMBO J. 2008;27:522–534
  23. Sorli SC, Le Gonidec S, Knibiehler B, Audigier Y. Apelin is a potent activator of tumour neoangiogenesis. Oncogene. 2007;26:7692–7699
  24. Principe A, Melgar-Lesmes P, Fernandez-Varo G, Ruiz del Arbol L, Ros J, Morales-Ruiz M, et al. The hepatic apelin system: a new therapeutic target for liver disease. Hepatology. 2008;48:1193–1201
  25. Sorli SC, Van den Berghe L, Masri B, Knibiehler B, Audigier Y. Therapeutic potential of interfering with apelin signalling. Drug Discov Today. 2006;11:1100–1106
  26. Fernandez M, Garcia-Pagan JC, Casadevall M, Bernadich C, Piera C, Whittle BJ, et al. Evidence against a role for inducible nitric oxide synthase in the hyperdynamic circulation of portal hypertensive rats. Gastroenterology. 1995;108:1487–1495
  27. Lee DK, Saldivia VR, Nguyen T, Cheng R, George SR, O’Dowd BF. Modification of the terminal residue of apelin-13 antagonizes its hypotensive action. Endocrinology. 2005;146:231–236
  28. Fernandez M, Garcia-Pagan JC, Casadevall M, Mourelle MI, Pique JM, Bosch J, et al. Acute and chronic cyclooxygenase blockade in portal hypertensive rats: influence on nitric oxide biosynthesis. Gastroenterology. 1996;110:1529–1535
  29. De Falco M, De Luca L, Onori N, Cavallotti I, Artigiano F, Esposito V, et al. Apelin expression in normal human tissues. In Vivo. 2002;16:333–336
  30. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–408
  31. Kleinz MJ, Davenport AP. Emerging roles of apelin in biology and medicine. Pharmacol Ther. 2005;107:198–211
  32. Hashimoto T, Kihara M, Ishida J, Imai N, Yoshida S, Toya Y, et al. Apelin stimulates myosin light chain phosphorylation in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2006;26:1267–1272
  33. Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology. 2002;35:478–491
  34. Fernandez M, Bonkovsky HL. Increased heme oxygenase-1 gene expression in liver cells and splanchnic organs from portal hypertensive rats. Hepatology. 1999;29:1672–1679
  35. Bendtzen K. Interleukin 1, interleukin 6 and tumor necrosis factor in infection, inflammation and immunity. Immunol Lett. 1988;19:183–191
  36. Albillos A, de la Hera A, Alvarez-Mon M. Serum lipopolysaccharide-binding protein prediction of severe bacterial infection in cirrhotic patients with ascites. Lancet. 2004;363:1608–1610
  37. Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun. 1998;251:471–476
  38. O’Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, et al. A human gene that shows identity with the gen encoding the angiotensin receptor is located on chromosome 11. Gene. 1993;136:355–360
  39. Lee DK, Cheng R, Nguyen T, Fan T, Kariyawasam AP, Liu Y, et al. Characterization of apelin, the ligand for the APJ receptor. J Neurochem. 2000;74:34–41
  40. Hosoya M, Kawamata Y, Fukusumi S, Fujii R, Habata Y, Hinuma S, et al. Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin. J Biol Chem. 2000;275:21061–21067
  41. Klos KS, Wyszomierski SL, Sun M, Tan M, Zhou X, Li P, et al. ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells. Cancer Res. 2006;66:2028–2037
  42. Katugampola SD, Maguire JJ, Matthewson SR, Davenport AP. [(125)I]-(Pyr(1))Apelin-13 is a novel radioligand for localizing the APJ orphan receptor in human and rat tissues with evidence for a vasoconstrictor role in man. Br J Pharmacol. 2001;132:1255–1260
  43. Ishida J, Hashimoto T, Hashimoto Y, Nishiwaki S, Iguchi T, Harada S, et al. Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo. J Biol Chem. 2004;279:26274–26279
  44. Tatemoto K, Takayama K, Zou MX, Kumaki I, Zhang W, Kumano K, et al. The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul Pept. 2001;99:87–92
  45. Cheng X, Cheng XS, Pang CC. Venous dilator effect of apelin, an endogenous peptide ligand for the orphan APJ receptor, in conscious rats. Eur J Pharmacol. 2003;470:171–175
  46. Charles CJ, Rademaker MT, Richards AM. Apelin-13 induces a biphasic haemodynamic response and hormonal activation in normal conscious sheep. J Endocrinol. 2006;189:701–710
  47. Salcedo A, Garijo J, Monge L, Fernandez N, Garcia-Villalon AL, Sanchez-Turrion V, et al. Apelin effects in human splanchnic arteries. Role of nitric oxide and prostanoids. Regul Pept. 2007;144:50–55

 The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this paper.

PII: S0168-8278(08)00765-4

doi: 10.1016/j.jhep.2008.09.019

Journal of Hepatology
Volume 50, Issue 2 , Pages 296-305 , February 2009