Skip to main content

Advertisement

Log in

Vasculopathy in type 2 diabetes mellitus: role of specific angiogenic modulators

  • Original Paper
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

Type 2 diabetes mellitus (T2DM) is largely defined by hyperglycemia that promotes vascular complications. Abnormal angiogenesis has been claimed to have a role in this disease. This study aimed to investigate serum levels of both conventional and other markers of angiogenesis not well studied before in diabetes, and to correlate findings with age of the patients, glycemic control, presence of microvascular complications, and oxidative stress. Thirty-eight patients with T2DM and 13 age- and sex-matched healthy persons representing controls were recruited. Serum levels of basic fibroblast growth factor (b-FGF) was measured by immunosorbent assay kit; advanced glycosylation end products, platelet-derived endothelial cell growth factor (PD-ECGF), cathepsin-D (CD), gangliosides, hyaluronic acid (HA), nitric oxide (NO), lipid peroxides (LPER), superoxide dismutase, and total thiols by chemical methods; and copper (Cu) by atomic absorption flame photometry. Advanced glycosylation end products and angiogenic factors (b-FGF, PD-ECGF, CD, gangliosides, HA, and Cu) were significantly higher in patients than controls. Oxidative stress markers, NO, and LPER were significantly higher while total thiols were significantly lower in patients than controls. These changes were more pronounced with age, poor glycemic control, and presence of microvascular complications. Angiogenesis dysfunction coinciding with elevated levels of many angiogenic growth factors may point to their malfunctioning due to oxidative stress and/or protein glycation at the factor and the receptor levels. This necessitates further investigations.

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

  1. Ahmed N, Thornalley PJ (2007) Advanced glycation end products: what is their relevance to diabetic complications. Diab Obes Metab 9:233–245

    Article  CAS  Google Scholar 

  2. Babaei S, Teichert-Kuliszewska K, Monge JC, Mohamed F, Bendeck MP, Stewart DJ (1998) Role of nitric oxide in the angiogenic response in vitro to basic fibroblast growth factor. Circ Res 82:1007–1015

    PubMed  CAS  Google Scholar 

  3. Bach MH, Sadoun E, Reed MJ (2005) Defects in activation of nitric oxide synthases occur during delayed angiogenesis in aging. Mech Ageing Dev 126:467–473

    Article  PubMed  CAS  Google Scholar 

  4. Barrett AJ (1970) Cathepsin D. Purification of isoenzymes from human and chicken liver. Biochem J 117(3):601–607

    PubMed  CAS  Google Scholar 

  5. Bejma J, Ji LL (1999) Aging and acute exercise enhance free radical generation in rat skeletal muscle. J Appl Physiol 87(1):465–470

    PubMed  CAS  Google Scholar 

  6. Berchem G, Glondu M, Gleizes M, Brouillet JP, Vignon F, Garcia M, Liaudet-Coopman E (2002) Cathepsin-D affects multiple tumor progression steps in vivo: proliferation, angiogenesis and apoptosis. Oncogene 21(38):5951–5955

    Article  PubMed  CAS  Google Scholar 

  7. Briozzo P, Badet J, Capony F, Pieri I, Montcourrier P, Barritault D, Rochefort H (1991) MCF7 mammary cancer cells respond to bFGF and internalize it following its release from extracellular matrix: a permissive role of cathepsin D. Exp Cell Res 194(2):252–259

    Article  PubMed  CAS  Google Scholar 

  8. Brown NS, Jones A, Fujiyama C, Harris AL, Bicknell R (2000) Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors. Cancer Res 60(22):6298–6302

    PubMed  CAS  Google Scholar 

  9. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865):813–820

    Article  PubMed  CAS  Google Scholar 

  10. Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625

    Article  PubMed  CAS  Google Scholar 

  11. Calhau C, Santos A (2009) Oxidative stress in the metabolic syndrome. In: Soares R, Costa C (eds) Oxidative stress, inflammation and angiogenesis in metabolic syndrome. Springer, The Netherlands, pp 33–63

    Chapter  Google Scholar 

  12. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257

    Article  PubMed  CAS  Google Scholar 

  13. de Bruin M, Temmink OH, Hoekman K, Pinedo HM, Peters GJ (2006) Role of platelet derived endothelial cell growth factor/thymidine phosphorylase in health and disease. Cancer Ther 4:99–124

    Google Scholar 

  14. Detillieux KA, Sheikh F, Kardami E, Cattini PA (2003) Biological activities of fibroblast growth factor-2 in the adult myocardium. Cardiovasc Res 57:8–19

    Article  PubMed  CAS  Google Scholar 

  15. Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 2:70–77

    Article  Google Scholar 

  16. El-Remessy A, Abou-Mohamed G, Caldwell RW, Caldwell RB (2003) High glucose increases tyrosine nitration and superoxide anion formation in endothelial cells: role of eNOS uncoupling and aldose reductase activation. Invest Ophthalmol Vis Sci 44:3135–3143

    Article  PubMed  Google Scholar 

  17. Fukui T, Noma T, Mizushige K, Aki Y, Kimura S, Abe Y (2000) Dietary troglitazone decreases oxidative stress in early stage type II diabetic rats. Life Sci 66:2043–2049

    Article  PubMed  CAS  Google Scholar 

  18. Grau A, Codony R, Rafecas M, Barroeta AC, Guardiola F (2000) Lipid hydroperoxide determination in dark chicken meat through a ferrous oxidation-xylenol orange method. J Agric Food Chem 48(9):4136–4143

    Article  PubMed  CAS  Google Scholar 

  19. Greiling H (1961) A new colorimetric method for enzymatic determination of hyaluronic acid. Z Rheumaforsch 20:298–302

    PubMed  CAS  Google Scholar 

  20. Hameed A, Malik S, Sharif FR, Ahmed N, Nurjis F, Ali S, Qureshi JA (2002) Diabetic complications: influence of age, sex, family history, duration, glycemic control and obesity. Online J Biol Sci 2(10):710–714

    Google Scholar 

  21. Hu GF (1998) Copper stimulates proliferation of human endothelial cells under culture. J Cell Biochem 69(3):326–335

    Article  PubMed  CAS  Google Scholar 

  22. Koga K, Yamagishi S, Okamoto T, Inagaki Y, Amano S, Takeuchi M, Makita Z (2002) Serum levels of glucose-derived advanced glycation end products are associated with the severity of diabetic retinopathy in type 2 diabetic patients without renal dysfunction. Int J Clin Pharmacol Res 22(1):13–17

    PubMed  CAS  Google Scholar 

  23. Larke RP, Froese GJ, Devine RD, Petruk MW (1988) Comprehensive seroepidemiologic study of hepatitis B virus infection in the Northwest Territories of Canada. Arct Med Res 47(1):711–713

    Google Scholar 

  24. Maritim AC, Sanders RA, Watkins JB III (2003) Diabetes, oxidative stress, and antioxidants: a review. J Biochem Mol Toxicol 17:24–38

    Article  PubMed  CAS  Google Scholar 

  25. Martin A, Komada MR, Sane DC (2003) Abnormal angiogenesis in diabetes mellitus. Med Res Rev 23:117–145

    Article  PubMed  CAS  Google Scholar 

  26. McAuslan BR, Reilly W (1980) Endothelial cell phagokinesis in response to specific metal ions. Exp Cell Res 130(1):147–157

    Article  PubMed  CAS  Google Scholar 

  27. Misra HP, Fridovich I (1972) The generation of superoxide radical during the autoxidation of hemoglobin. J Biol Chem 247(21):6960–6962

    PubMed  CAS  Google Scholar 

  28. Murphy JF, Lennon F, Steele C, Kelleher D, Fitzgerald D, Long AC (2005) Engagement of CD44 modulates cyclooxygenase induction, VEGF generation and proliferation in human vascular endothelial cells. FASEB J 19:446–448

    PubMed  CAS  Google Scholar 

  29. Nagai Y (1995) Functional roles of gangliosides in bio-signaling. Behav Brain Res 66:99–104

    Article  PubMed  CAS  Google Scholar 

  30. Nayeemunnisa (2008) Proteolytic activity in the brain of alloxan diabetic rats: presence of a proteolytic activator in the cerebral extract. Int J Diabetes Dev Ctries 28(3):83–85

    Article  PubMed  CAS  Google Scholar 

  31. Ohshiro Y, Takasu N (2006) Molecular mechanism of diabetic nephropathy. Nippon Rinsho 64:997–1003

    PubMed  Google Scholar 

  32. Pardue EL, Ibrahim S, Ramamurthi A (2008) Role of hyaluronan in angiogenesis and its utility to angiogenic tissue engineering. Organogenesis 4(4):203–214

    Article  PubMed  Google Scholar 

  33. Plucinsky MC, Prorok JJ, Alhadeff JA (1986) Variant serum beta-hexosaminidase as a biochemical marker of malignancy. Cancer 58(7):1484–1487

    Article  PubMed  CAS  Google Scholar 

  34. Poggioli S, Hilaire B, Friguet B (2002) Age-related increase of proteins glycation in peripheral blood lymphocytes is restricted to preferential target proteins. Exp Geront 37:1207–1215

    Article  CAS  Google Scholar 

  35. Roberts DD, Isenberg JS, Ridnour LA, Wink DA (2007) Nitric oxide and its gatekeeper thrombospondin-1 in tumor angiogenesis. Clin Cancer Res 13(3):795–798

    Article  PubMed  CAS  Google Scholar 

  36. Saharinen P, Alitalo K (2003) Double target for tumor mass destruction. J Clin Invest 111:1277–1280

    PubMed  CAS  Google Scholar 

  37. Sakuaba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S (2002) Reduced β-cell mass and expression of oxidative stress related DNA damage in the islet of Japanese type II diabetic patients. Diabetologia 45:85–96

    Article  Google Scholar 

  38. Scocca JJ (1978) Pyrimidine nucleoside phosphorylase from Haemophilus influenzae. Meth Enzymol 51:432–437

    Article  PubMed  CAS  Google Scholar 

  39. Skrzydlewska E, Sulkowska M, Wincewicz A, Koda M, Sulkowski S (2005) Evaluation of serum cathepsin B and D in relation to clinicopathological staging of colorectal cancer. World J Gastroenterol 11(27):4225–4229

    PubMed  CAS  Google Scholar 

  40. Slavin J (1995) Fibroblast growth factors: at the heart of angiogenesis. Cell Biol Int 19:431–444

    Article  PubMed  CAS  Google Scholar 

  41. Tanihara H, Inatani M, Honda Y (1997) Growth factors and their receptors in the retina and pigmented epithelium. In: Osborne N, Chader G (eds) Progress in retinal and eye research. Pergamon, Oxford, pp 271–301

    Google Scholar 

  42. Thornalley PJ, Battah S, Ahmed N, Karachalias N, Agalou S, Babaei-Jadidi R, Dawnay A (2003) Quantitative screening of advanced glycation end-products in cellular and extracellular proteins by tandem mass spectrometry. Biochem J 375:581–592

    Article  PubMed  CAS  Google Scholar 

  43. van Bezooijen RL, Que I, Ederveen AG, Kloosterboer HJ, Papapoulos SE, Lowik CW (1998) Plasma nitrate + nitrite level are regulated by ovarian steroids but do not correlate with trabecular bone mineral density in rats. J Endocrinol 159:27–34

    Article  PubMed  Google Scholar 

  44. Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinses—structure, function, and biochemistry. Circ Res 92:827–839

    Article  PubMed  CAS  Google Scholar 

  45. Walter RM Jr, Uriu-Hare JY, Olin KL, Oster MH, Anawalt BD, Critchfield JW, Keen CL (1991) Copper, zinc, manganese, and magnesium status and complications of diabetes mellitus. Diab Care 14(11):1050–1056

    Article  Google Scholar 

  46. Wang SY, Friedman M, Johnson RG, Weintraub RM, Sellke FW (1994) Adrenergic regulation of coronary microcirculation after extracorporeal circulation and crystalloid cardioplegia. Am J Physiol 267:H2462–H2470

    PubMed  CAS  Google Scholar 

  47. Wang XH, Chen SF, Jin HM, Hu RM (2009) Differential analyses of angiogenesis and expression of growth factors in micro- and macrovascular endothelial cells of type 2 diabetic rats. Life Sci 84:240–249

    Article  PubMed  CAS  Google Scholar 

  48. Wautier JL, Schmidt AM (2004) Protein glycation. Circ Res 95:233–238

    Article  PubMed  CAS  Google Scholar 

  49. Weber M, Mohand-Said S, Hicks D, Dreyfus H, Sahel JA (1996) Monosialoganglioside GM1 reduces ischemia-reperfusion-induced injury in the rat retina. Invest Ophthalmol Vis Sci 37:267–273

    PubMed  CAS  Google Scholar 

  50. West DC, Kumar S (1988) Endothelial cell proliferation and diabetic retinopathy. Lancet 1:715–716

    Article  PubMed  CAS  Google Scholar 

  51. Witek B, Król T, Kołataj A, Ochwanowska E, Stanisławska I, Slewa A (2001) The insulin, glucose and cholesterol level and activity of lysosomal enzymes in the course of the model alloxan diabetes. Neuro Endocrinol Lett 22(4):238–242

    PubMed  CAS  Google Scholar 

  52. Yamagishi S, Nakamura K, Imaizumi T (2005) Advanced glycation end products (AGEs) and diabetic vascular complications. Curr Diab Rev 1(1):93–106

    Article  CAS  Google Scholar 

  53. Yan HD, Li XZ, Xie JM, Li M (2007) Effects of advanced glycation end products on renal fibrosis and oxidative stress in cultured NRK-49F cells. Chin Med J (Engl) 120(9):787–793

    CAS  Google Scholar 

  54. Yang HT, Yan Z, Abraham JA, Terjung RL (2001) VEGF121- and bFGF-induced increase in collateral blood flow requires normal nitric oxide production. Am J Physiol Heart Circ Physiol 280:H1097–H1104

    PubMed  CAS  Google Scholar 

  55. Yang HT (2007) Effect of aging on angiogenesis and arteriogenesis. Curr Cardiol Rev 3:65–74

    Article  CAS  Google Scholar 

  56. Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF beta and promotes tumor invasion and angiogenesis. Genes Dev 14:163–176

    PubMed  Google Scholar 

  57. Zargar AH, Shah NA, Masoodi SR, Masoodi SR, Laway BA, Wani AI, Dar FA (1998) Copper, zinc and magnesium levels in non insulin dependent diabetes mellitus. Postgrad Med J 74:665–668

    Article  PubMed  CAS  Google Scholar 

  58. Zhang Y, Li J, Partovian C, Sellke FW, Simons M (2003) Syndecan-4 modulates basic fibroblast growth factor 2 signaling in vivo. Am J Physiol Heart Circ Physiol 284:H2078–H2082

    PubMed  CAS  Google Scholar 

  59. Zimering MB, Andersonc RJ, Luoc P, Moritz TE (2008) Plasma basic fibroblast growth factor is correlated with plasminogen activator inhibitor-1 concentration in adults from the Veterans Affairs Diabetes Trial. Metab Clin Exp 57:1563–1569

    PubMed  CAS  Google Scholar 

Download references

Conflicts of interest

There are no conflicts of interest.

Limitation of the study

The small number of patients and study being cross-sectional rather than longitudinal are the major limitations of this study. The major cause was the limitation of the local research resources and budget to cover a few hundred patients required for proper sample size and an elaborate longitudinal and may be interference study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Enas A. Hamed.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hamed, E.A., Zakary, M.M., Abdelal, R.M. et al. Vasculopathy in type 2 diabetes mellitus: role of specific angiogenic modulators. J Physiol Biochem 67, 339–349 (2011). https://doi.org/10.1007/s13105-011-0080-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-011-0080-8

Keywords

Navigation