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PPARγ ligands, rosiglitazone and pioglitazone, inhibit bFGF- and VEGF-mediated angiogenesis

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Abstract

Objective

To study the effect of peroxisome proliferator-activated receptor-gamma (PPARγ) agonists, pioglitazone and rosiglitazone, on vascular endothelial growth factor (VEGF)- and basic fibroblast growth factor (bFGF)-induced angiogenesis and on endothelial cell migration.

Methods

Chick chorioallantoic membrane (CAM) model was used to evaluate the efficacy of pioglitazone and rosiglitazone on VEGF- and bFGF-induced angiogenesis. In addition, the effect of pioglitazone and rosiglitazone on endothelial cell migration was evaluated using 8 mm pore filter to a feeder layer containing vitronectin as chemoattractant.

Results

Pioglitazone and rosiglitazone inhibited the pro-angiogenic effects of bFGF and VEGF in the CAM model significantly (< 0.001) to the same extent. Endothelial cell migration was also inhibited by both pioglitazone and rosiglitazone (< 0.001).

Conclusions

These results suggest that PPARγ ligands, pioglitazone and rosiglitazone, in addition to their important regulatory role in adipogenesis and inflammation, possess anti-angiogenic properties. Thus, PPARγ ligands may be useful in the treatment of diabetic retinopathy, macular degeneration, and other ocular disorders and may lower the risk to develop cancer in diabetic patients.

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References

  1. Laukkanen JA, Laaksonen DE, Niskanen L, Pukkala E, Hakkarainen A, Salonen JT (2004) Metabolic syndrome and the risk of prostate cancer in Finnish men: a population-based study. Cancer Epidemiol Biomarkers Prev 13:1646–1650

    PubMed  CAS  Google Scholar 

  2. Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ (2004) Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 159:1160–1167. doi:10.1093/aje/kwh161

    Article  PubMed  Google Scholar 

  3. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N (2004) Preliminary communication: glycated hemoglobin, diabetes, and incident colorectal cancer in men and women: a prospective analysis from the European prospective investigation into cancer-Norfolk study. Cancer Epidemiol Biomarkers Prev 13:915–919

    PubMed  Google Scholar 

  4. Inoue M, Iwasaki M, Otani T, Sasazuki S, Noda M, Tsugane S (2006) Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med 166:1871–1877. doi:10.1001/archinte.166.17.1871

    Article  PubMed  Google Scholar 

  5. Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP et al (2008) Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 47:1856–1862. doi:10.1002/hep.22251

    Article  PubMed  Google Scholar 

  6. Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM et al (1998) Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med 4:1058–1061. doi:10.1038/2042

    Article  PubMed  CAS  Google Scholar 

  7. Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin KJ, Zhang M et al (1998) Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell 1:465–470. doi:10.1016/S1097-2765(00)80047-7

    Article  PubMed  CAS  Google Scholar 

  8. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM (1998) PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241–252. doi:10.1016/S0092-8674(00)81575-5

    Article  PubMed  CAS  Google Scholar 

  9. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM (1998) Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 93:229–240. doi:10.1016/S0092-8674(00)81574-3

    Article  PubMed  CAS  Google Scholar 

  10. Escher P, Wahli W (2000) Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutat Res 448:121–138. doi:10.1016/S0027-5107(99)00231-6

    PubMed  CAS  Google Scholar 

  11. Yajima K, Hirose H, Fujita H, Seto Y, Fujita H, Ukeda K et al (2003) Combination therapy with PPARgamma and PPARalpha agonists increases glucose-stimulated insulin secretion in db/db mice. Am J Physiol Endocrinol Metab 284:E966–E971

    PubMed  CAS  Google Scholar 

  12. Keshamouni VG, Arenberg DA, Reddy RC, Newstead MJ, Anthwal S, Standiford TJ (2005) PPAR-gamma activation inhibits angiogenesis by blocking ELR + CXC chemokine production in non-small cell lung cancer. Neoplasia 7:294–301. doi:10.1593/neo.04601

    Article  PubMed  CAS  Google Scholar 

  13. Kolak M, Yki-Jarvinen H, Kannisto K, Tiikkainen M, Hamsten A, Eriksson P et al (2007) Effects of chronic rosiglitazone therapy on gene expression in human adipose tissue in vivo in patients with type 2 diabetes. J Clin Endocrinol Metab 92:720–724. doi:10.1210/jc.2006-1465

    Article  PubMed  CAS  Google Scholar 

  14. Jha RJ (1999) Thiazolidinediones–the new insulin enhancers. Clin Exp Hypertens 21:157–166

    Article  PubMed  CAS  Google Scholar 

  15. Lebovitz HE, Banerji MA (2001) Insulin resistance and its treatment by thiazolidinediones. Recent Prog Horm Res 56:265–294. doi:10.1210/rp.56.1.265

    Article  PubMed  CAS  Google Scholar 

  16. (2000) Actos (pioglitazone HCL) provides a safe, effective alternative for patients formerly taking Rezulin. Diabetes Technol Ther 2:290–291

  17. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438:932–936. doi:10.1038/nature04478

    Article  PubMed  CAS  Google Scholar 

  18. Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674. doi:10.1038/386671a0

    Article  PubMed  CAS  Google Scholar 

  19. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62. doi:10.1126/science.1104819

    Article  PubMed  CAS  Google Scholar 

  20. De Luca A, Carotenuto A, Rachiglio A, Gallo M, Maiello MR, Aldinucci D et al (2008) The role of the EGFR signaling in tumor microenvironment. J Cell Physiol 214:559–567. doi:10.1002/jcp.21260

    Article  PubMed  CAS  Google Scholar 

  21. Mousa SA, O’Connor LJ, Bergh JJ, Davis FB, Scanlan TS, Davis PJ (2005) The proangiogenic action of thyroid hormone analogue GC-1 is initiated at an integrin. J Cardiovasc Pharmacol 46:356–360. doi:10.1097/01.fjc.0000175438.94906.a0

    Article  PubMed  CAS  Google Scholar 

  22. Colman RW, Pixley RA, Sainz IM, Song JS, Isordia-Salas I, Muhamed SN et al (2003) Inhibition of angiogenesis by antibody blocking the action of proangiogenic high-molecular-weight kininogen. J Thromb Haemost 1:164–170. doi:10.1046/j.1538-7836.2003.00025.x

    Article  PubMed  CAS  Google Scholar 

  23. Bozarth J, Penno M (1997) SAM: an improved method for the quantitation of cellular migration–role of avb3 integrin in endothelial and smooth muscle cell migration. Methods Cell Sci 19:179–187. doi:10.1023/A:1009789416463

    Article  Google Scholar 

  24. Lemberger T, Desvergne B, Wahli W (1996) Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology. Annu Rev Cell Dev Biol 12:335–363. doi:10.1146/annurev.cellbio.12.1.335

    Article  PubMed  CAS  Google Scholar 

  25. Fruchart JC, Duriez P, Staels B (1999) Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. Curr Opin Lipidol 10:245–257. doi:10.1097/00041433-199906000-00007

    Article  PubMed  CAS  Google Scholar 

  26. Suchanek KM, May FJ, Robinson JA, Lee WJ, Holman NA, Monteith GR et al (2002) Peroxisome proliferator-activated receptor alpha in the human breast cancer cell lines MCF-7 and MDA-MB-231. Mol Carcinog 34:165–171. doi:10.1002/mc.10061

    Article  PubMed  CAS  Google Scholar 

  27. Engel J, Rabba J, Schild D (1996) A transient, RCK4-like K+ current in cultured Xenopus olfactory bulb neurons. Pflugers Arch 432:845–852. doi:10.1007/s004240050207

    Article  PubMed  CAS  Google Scholar 

  28. Xin X, Yang S, Kowalski J, Gerritsen ME (1999) Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem 274:9116–9121. doi:10.1074/jbc.274.13.9116

    Article  PubMed  CAS  Google Scholar 

  29. Marx N, Bourcier T, Sukhova GK, Libby P, Plutzky J (1999) PPARgamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARgamma as a potential mediator in vascular disease. Arterioscler Thromb Vasc Biol 19:546–551

    PubMed  CAS  Google Scholar 

  30. Satoh H, Tsukamoto K, Hashimoto Y, Hashimoto N, Togo M, Hara M et al (1999) Thiazolidinediones suppress endothelin-1 secretion from bovine vascular endothelial cells: a new possible role of PPARgamma on vascular endothelial function. Biochem Biophys Res Commun 254:757–763. doi:10.1006/bbrc.1998.0126

    Article  PubMed  CAS  Google Scholar 

  31. Panigrahy D, Huang S, Kieran MW, Kaipainen A (2005) PPARgamma as a therapeutic target for tumor angiogenesis and metastasis. Cancer Biol Ther 4:687–693

    Article  PubMed  CAS  Google Scholar 

  32. Murata T, He S, Hangai M, Ishibashi T, Xi XP, Kim S et al (2000) Peroxisome proliferator-activated receptor-gamma ligands inhibit choroidal neovascularization. Invest Ophthalmol Vis Sci 41:2309–2317

    PubMed  CAS  Google Scholar 

  33. Goetze S, Eilers F, Bungenstock A, Kintscher U, Stawowy P, Blaschke F et al (2002) PPAR activators inhibit endothelial cell migration by targeting Akt. Biochem Biophys Res Commun 293:1431–1437. doi:10.1016/S0006-291X(02)00385-6

    Article  PubMed  CAS  Google Scholar 

  34. Goetze S, Bungenstock A, Czupalla C, Eilers F, Stawowy P, Kintscher U et al (2002) Leptin induces endothelial cell migration through Akt, which is inhibited by PPARgamma-ligands. Hypertension 40:748–754. doi:10.1161/01.HYP.0000035522.63647.D3

    Article  PubMed  CAS  Google Scholar 

  35. Huang H, Campbell SC, Bedford DF, Nelius T, Veliceasa D, Shroff EH et al (2004) Peroxisome proliferator-activated receptor gamma ligands improve the antitumor efficacy of thrombospondin peptide ABT510. Mol Cancer Res 2:541–550

    PubMed  CAS  Google Scholar 

  36. Panigrahy D, Singer S, Shen LQ, Butterfield CE, Freedman DA, Chen EJ et al (2002) PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest 110:923–932

    PubMed  CAS  Google Scholar 

  37. Sierra-Honigmann MR, Nath AK, Murakami C, Garcia-Cardena G, Papapetropoulos A, Sessa WC et al (1998) Biological action of leptin as an angiogenic factor. Science 281:1683–1686. doi:10.1126/science.281.5383.1683

    Article  PubMed  CAS  Google Scholar 

  38. Giannini S, Serio M, Galli A (2004) Pleiotropic effects of thiazolidinediones: taking a look beyond antidiabetic activity. J Endocrinol Invest 27:982–991

    PubMed  CAS  Google Scholar 

  39. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027. doi:10.1200/JCO.2005.06.081

    Article  PubMed  CAS  Google Scholar 

  40. Fahmy RG, Dass CR, Sun LQ, Chesterman CN, Khachigian LM (2003) Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth. Nat Med 9:1026–1032. doi:10.1038/nm905

    Article  PubMed  CAS  Google Scholar 

  41. Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS et al (1993) Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 362:841–844. doi:10.1038/362841a0

    Article  PubMed  CAS  Google Scholar 

  42. Yan W, Bentley B, Shao R (2008) Distinct angiogenic mediators are required for basic fibroblast growth factor- and vascular endothelial growth factor-induced angiogenesis: the role of cytoplasmic tyrosine kinase c-Abl in tumor angiogenesis. Mol Biol Cell 19:2278–2288. doi:10.1091/mbc.E07-10-1068

    Article  PubMed  CAS  Google Scholar 

  43. Michalik L, Desvergne B, Wahli W (2004) Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat Rev Cancer 4:61–70. doi:10.1038/nrc1254

    Article  PubMed  CAS  Google Scholar 

  44. Kaipainen A, Kieran MW, Huang S, Butterfield C, Bielenberg D, Mostoslavsky G (2007) PPARalpha deficiency in inflammatory cells suppresses tumor growth. PLoS ONE 2:e260. doi:10.1371/journal.pone.0000260

    Article  PubMed  CAS  Google Scholar 

  45. Panigrahy D, Kaipainen A, Huang S, Butterfield CE, Barnes CM, Fannon M et al (2008) PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. Proc Natl Acad Sci USA 105:985–990. doi:10.1073/pnas.0711281105

    Article  PubMed  CAS  Google Scholar 

  46. Strickler HD, Wylie-Rosett J, Rohan T, Hoover DR, Smoller S, Burk RD et al (2001) The relation of type 2 diabetes and cancer. Diabetes Technol Ther 3:263–274. doi:10.1089/152091501300209633

    Article  PubMed  CAS  Google Scholar 

  47. Govindarajan R, Ratnasinghe L, Simmons DL, Siegel ER, Midathada MV, Kim L et al (2007) Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol 25:1476–1481. doi:10.1200/JCO.2006.07.2777

    Article  PubMed  CAS  Google Scholar 

  48. Shen LQ, Child A, Weber GM, Folkman J, Aiello LP (2008) Rosiglitazone and delayed onset of proliferative diabetic retinopathy. Arch Ophthalmol 126:793–799. doi:10.1001/archopht.126.6.793

    Article  PubMed  Google Scholar 

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Correspondence to Shaker A. Mousa.

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Aljada, A., O’Connor, L., Fu, YY. et al. PPARγ ligands, rosiglitazone and pioglitazone, inhibit bFGF- and VEGF-mediated angiogenesis. Angiogenesis 11, 361–367 (2008). https://doi.org/10.1007/s10456-008-9118-0

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  • DOI: https://doi.org/10.1007/s10456-008-9118-0

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