Long-Term Complications in Diabetes Mellitus and the Interrelationship of Blood Vessel Formation, Endothelial Progenitor Cells, and gDNA Methylation

  • Michael P. SarrasJr.Email author
  • Alexey A. Leontovich
Reference work entry


Diabetes mellitus is a disease of metabolic dysregulation resulting in microvascular and macrovascular complications. As such, the endothelial cell (EC) is a fundamental cell type targeted by the hyperglycemic (HG) episodes that occur in the disease, and this causes abnormalities in the basic process of blood vessel formation (BVF). These abnormalities in BVF are seen in the acute and chronic states of DM, with the latter chronic effects termed “metabolic memory” (MM). Abnormalities in BVF in DM are based on abnormalities in the processes of vasculargenesis and subsequent angiogenesis. In humans, vasculargenesis is dependent on endothelial progenitor cells (EPCs), and these cells have been reported to be dysfunctional in DM. Studies in an animal model of DM and MM have shown that hyperglycemia induces epigenetic changes observed as gDNA hypomethylation in a loci-specific but genome-wide fashion. The role of these gDNA methylation changes as a contributing factor in the long-term complications of DM seen in MM is unclear, but may relate to dysfunctions in mechanisms involved in the regulation of gene expression. This chapter provides an overview of the interrelation of (1) DM/MM, (2) BVF, (3) EPC, and (4) gDNA methylation and proposes mechanisms to explain these relationships and experimental approaches to test the validity of these mechanisms.


Diabetes mellitus Metabolic memory Epigenetics gDNA methylation Hypomethylation Bioinformatics Blood vessel formation Endothelial cells Endothelial progenitor cells Regulation genes of blood vessel formation 

List of Abbreviations




Advanced glycation end products


Blood vessel formation


Cytosine-phosphate-guanine (a dinucleotide)


Connective tissue growth factor


Cardiovascular system


Diabetes mellitus


Endothelial cells


Endothelial progenitor cells


Metabolic memory


Methylated regions (of gDNA)


Human umbilical cord endothelial cells




Open reading frame


Reactive oxygen species


Transcription factor


Transcription start site


  1. Antonio N, Fernandes R, Soares A, Soares F, Lopes A, Carvalheiro T, Paiva A, Pego GM, Providencia LA, Goncalves L, Ribeiro CF (2014) Reduced levels of circulating endothelial progenitor cells in acute myocardial infarction patients with diabetes or pre-diabetes: accompanying the glycemic continuum. Cardiovasc Diabetol 13:101CrossRefGoogle Scholar
  2. Baynes JW (1991) Role of oxidative stress in development of complications in diabetes. Diabetes 40(4):405–412CrossRefGoogle Scholar
  3. Beach SR, Brody GH, Barton AW, Philibert RA (2016) Exploring genetic moderators and epigenetic mediators of contextual and family effects: from gene x environment to epigenetics. Dev Psychopathol:1–14Google Scholar
  4. Berezin AE, Samura TA, Kremzer AA, Berezina TA, Martovitskaya YV, Gromenko EA (2016) An association of serum vistafin level and number of circulating endothelial progenitor cells in type 2 diabetes mellitus patients. Diabetes Metab Syndr 10:205–212CrossRefGoogle Scholar
  5. Bjornsson HT, Fallin MD, Feinberg AP (2004) An integrated epigenetic and genetic approach to common human disease. Trends Genet: TIG 20(8):350–358CrossRefGoogle Scholar
  6. Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54(6):1615–1625CrossRefGoogle Scholar
  7. Caramori ML, Kim Y, Moore JH, Rich SS, Mychaleckyj JC, Kikyo N, Mauer M (2012) Gene expression differences in skin fibroblasts in identical twins discordant for type 1 diabetes. Diabetes 61(3):739–744CrossRefGoogle Scholar
  8. Carmeliet P (2005) Angiogenesis in life, disease and medicine. Nature 438(7070):932–936CrossRefGoogle Scholar
  9. Chong MS, Ng WK, Chan JK (2016) Concise review: endothelial progenitor cells in regenerative medicine: applications and challenges. Stem Cells Transl Med 5(4):530–538CrossRefGoogle Scholar
  10. Costa P, Soares R (2013) Neovascularization in diabetes and its complications. Unraveling the angiogenic paradox. Life Sci 92(22):1037–1045CrossRefGoogle Scholar
  11. Delaval K, Feil R (2004) Epigenetic regulation of mammalian genomic imprinting. Curr Opin Genet Dev 14(2):188–195CrossRefGoogle Scholar
  12. Dhliwayo N, Sarras M, Luczkowski E, Mason S, Intine R (2014) Parp inhibition prevents ten eleven translocase enzyme activation and hyperglycemia induced DNA methylation. Diabetes 63:3069–3076CrossRefGoogle Scholar
  13. Dolinoy DC, Jirtle RL (2008) Environmental epigenomics in human health and disease. Environ Mol Mutagen 49(1):4–8CrossRefGoogle Scholar
  14. Drela E, Stankowska K, Kulwas A, Rosc D (2012) Endothelial progenitor cells in diabetic foot syndrome. Adv Clin Exp Med 21(2):249–254PubMedGoogle Scholar
  15. Fadini GP, Miorin M, Facco M, Bonamico S, Baesso I, Grego F, Menegolo M, de Kreutzenberg SV, Tiengo A, Agostini C, Avogaro A (2005) Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol 45(9):1449–1457CrossRefGoogle Scholar
  16. Fadini GP, Ferraro F, Quaini F, Asahara T, Madeddu P (2014) Concise review: diabetes, the bone marrow niche, and impaired vascular regeneration. Stem Cells Transl Med 3(8):949–957CrossRefGoogle Scholar
  17. Fernando CA, Conrad PA, Bartels CF, Marques T, To M, Balow SA, Nakamura Y, Warman ML (2010) Temporal and spatial expression of CCN genes in zebrafish. Dev Dyn 239(6):1755–1767CrossRefGoogle Scholar
  18. Franca CN, Amaral JB, Tuleta ID, Siviero F, Ferreira CE, Izar MC, Fonseca FA (2016) Challenges facing the use of endothelial progenitor cells in stem cell therapies. Crit Rev Eukaryot Gene Expr 26(2):161–162CrossRefGoogle Scholar
  19. Gluckman PD, Hanson MA, Beedle AS (2007) Non-genomic transgenerational inheritance of disease risk. Bioessays 29(2):145–154CrossRefGoogle Scholar
  20. Goerke SM, Obermeyer J, Plaha J, Stark GB, Finkenzeller G (2014) Endothelial progenitor cells from peripheral blood support bone regeneration by provoking an angiogenic response. Microvasc Res 98C:40–47Google Scholar
  21. Grutzmacher C, Park S, Zhao Y, Morrison ME, Sheibani N, Sorenson CM (2013) Aberrant production of extracellular matrix proteins and dysfunction in kidney endothelial cells with a short duration of diabetes. Am J Physiol Ren Physiol 304(1):F19–F30CrossRefGoogle Scholar
  22. He Y, Ecker JR (2015) Non-CG methylation in the human genome. Annu Rev Genomics Hum Genet 16:55–77CrossRefGoogle Scholar
  23. Heerboth S, Lapinska K, Snyder N, Leary M, Rollinson S, Sarkar S (2014) Use of epigenetic drugs in disease: an overview. Genet Epigenet 6:9–19CrossRefGoogle Scholar
  24. Ho L, Crabtree GR (2010) Chromatin remodelling during development. Nature 463(7280):474–484CrossRefGoogle Scholar
  25. Inzucchi S, Majumdar S (2015) Glycemic targets: what is the evidence? Med Clin North Am 99(1):47–67CrossRefGoogle Scholar
  26. Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, Cui H, Gabo K, Rongione M, Webster M, Ji H, Potash JB, Sabunciyan S, Feinberg AP (2009) The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet 41(2):178–186CrossRefGoogle Scholar
  27. Ivkovic S, Yoon BS, Popoff SN, Safadi FF, Libuda DE, Stephenson RC, Daluiski A, Lyons KM (2003) Connective tissue growth factor coordinates chondrogenesis and angiogenesis during skeletal development. Development 130(12):2779–2791CrossRefGoogle Scholar
  28. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33(Suppl):245–254CrossRefGoogle Scholar
  29. Jirtle RL, Sander M, Barrett JC (2000) Genomic imprinting and environmental disease susceptibility. Environ Health Perspect 108(3):271–278CrossRefGoogle Scholar
  30. Kouzarides T (2007) Chromatin modifications and their function. Cell 128(4):693–705CrossRefGoogle Scholar
  31. Kuiper EJ, Witmer AN, Klaassen I, Oliver N, Goldschmeding R, Schlingemann RO (2004) Differential expression of connective tissue growth factor in microglia and pericytes in the human diabetic retina. Br J Ophthalmol 88(8):1082–1087CrossRefGoogle Scholar
  32. Leontovich AAIRV, Sarras MP Jr (2016) Epigenetic studies point to DNA replication/repair genes as a basis for the heritable nature of long term complications in diabetes. J Diabetes Res 2016:1–10CrossRefGoogle Scholar
  33. Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, van Zonneveld AJ (2004) Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 53(1):195–199CrossRefGoogle Scholar
  34. Luttun A, Carmeliet G, Carmeliet P (2002) Vascular progenitors: from biology to treatment. Trends Cardiovasc Med 12(2):88–96CrossRefGoogle Scholar
  35. Martos SN, Tang WY, Wang Z (2015) Elusive inheritance: transgenerational effects and epigenetic inheritance in human environmental disease. Prog Biophys Mol Biol 118(1–2):44–54CrossRefGoogle Scholar
  36. Menegazzo L, Albiero M, Avogaro A, Fadini GP (2012) Endothelial progenitor cells in diabetes mellitus. Biofactors 38(3):194–202CrossRefGoogle Scholar
  37. Morgan DK, Whitelaw E (2008) The case for transgenerational epigenetic inheritance in humans. Mamm Genome: Off J Int Mamm Genome Soc 19(6):394–397CrossRefGoogle Scholar
  38. Mosammaparast N, Shi Y (2010) Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Annu Rev Biochem 79:155–179CrossRefGoogle Scholar
  39. Olsen AS, Sarras MP, Leontovich A, Intine RV (2012) Heritable transmission of diabetic metabolic memory in zebrafish correlates with and aberrant Gene expression. Diabetes 61(2):485–491CrossRefGoogle Scholar
  40. Peters EB, Liu B, Christoforou N, West JL, Truskey GA (2015) Umbilical cord blood-derived mononuclear cells exhibit Pericyte-like phenotype and support network formation of endothelial progenitor cells in vitro. Ann Biomed Eng 43:2552–2568CrossRefGoogle Scholar
  41. Pi L, Shenoy AK, Liu J, Kim S, Nelson N, Xia H, Hauswirth WW, Petersen BE, Schultz GS, Scott EW (2012) CCN2/CTGF regulates neovessel formation via targeting structurally conserved cystine knot motifs in multiple angiogenic regulators. FASEB J 26(8):3365–3379CrossRefGoogle Scholar
  42. Pirola L, Balcerczyk A, Tothill RW, Haviv I, Kaspi A, Lunke S, Ziemann M, Karagiannis T, Tonna S, Kowalczyk A, Beresford-Smith B, Macintyre G, Kelong M, Hongyu Z, Zhu J, El-Osta A (2011) Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells. Genome Res 21(10):1601–1615CrossRefGoogle Scholar
  43. Prattichizzo F, Giuliani A, Ceka A, Rippo MR, Bonfigli AR, Testa R, Procopio AD, Olivieri F (2015) Epigenetic mechanisms of endothelial dysfunction in type 2 diabetes. Clin Epigenetics 7(1):56CrossRefGoogle Scholar
  44. Putta S, Lanting L, Sun G, Lawson G, Kato M, Natarajan R (2012) Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy. J Am Soc Nephrol 23(3):458–469CrossRefGoogle Scholar
  45. Rakyan V K, Beyan H, Down T A, Hawa M I, Maslau S, Aden D, Daunay A, Busato F, Mein C A, Manfras B, Dias K R, Bell C G, Tost J +, Boehm B O, Beck S, Leslie R D. Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis. PLoS Genet 2011; 7(9): e1002300CrossRefGoogle Scholar
  46. Rando OJ (2012) Combinatorial complexity in chromatin structure and function: revisiting the histone code. Curr Opin Genet Dev 22(2):148–155CrossRefGoogle Scholar
  47. Ribatti D (2007) The discovery of endothelial progenitor cells. An historical review. Leuk Res 31(4):439–444CrossRefGoogle Scholar
  48. Riddle MC (2010) Effects of intensive glucose lowering in the management of patients with type 2 diabetes mellitus in the action to control cardiovascular risk in diabetes (ACCORD) trial. Circulation 122(8):844–846CrossRefGoogle Scholar
  49. Rodriguez H, Rafehi H, Bhave M, El-Osta A (2016) Metabolism and chromatin dynamics in health and disease. Mol Aspects Med 54:1–15CrossRefGoogle Scholar
  50. Roy S, Sala R, Cagliero E, Lorenzi M (1990) Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory. Proc Natl Acad Sci U S A 87(1):404–408CrossRefGoogle Scholar
  51. Sarras MP, Leontovich AA, Olsen AS, Intine RV (2013) Impaired tissue regeneration corresponds with altered expression of developmental genes that persists in the metabolic memory state of diabetic zebrafish. Wound Repair Regen: Off Publ Wound Heal Soc Eur Tissue Repair Soc 21(2):320–328CrossRefGoogle Scholar
  52. Sarras MP Jr, Mason S, McAllister G, Intine RV (2014) Inhibition of poly-ADP ribose polymerase enzyme activity prevents hyperglycemia-induced impairment of angiogenesis during wound healing. Wound Repair Regen 22(5):666–670CrossRefGoogle Scholar
  53. Shaw JE, Sicree RA, Zimmet PZ (2010) Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 87(1):4–14CrossRefGoogle Scholar
  54. Siekmann AF, Affolter M, Belting HG (2013) The tip cell concept 10 years after: new players tune in for a common theme. Exp Cell Res 319(9):1255–1263CrossRefGoogle Scholar
  55. Skinner MK, Manikkam M, Haque MM, Zhang B, Savenkova MI (2012) Epigenetic transgenerational inheritance of somatic transcriptomes and epigenetic control regions. Genome Biol 13(10):R91CrossRefGoogle Scholar
  56. Skyler JS, Bergenstal R, Bonow RO, Buse J, Deedwania P, Gale EAM, Howard BV, Kirkman MS, Kosiborod M, Reaven P, Sherwin RS, American Diabetes Association, American College of Cardiology Foundation, American Heart Association (2009) Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care 32(1):187–192CrossRefGoogle Scholar
  57. Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC (2002) Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106(22):2781–2786CrossRefGoogle Scholar
  58. Volkmar M, Dedeurwaerder S, Cunha DA, Ndlovu MN, Defrance M, Deplus R, Calonne E, Volkmar U, Igoillo-Esteve M, Naamane N, Del GS, Masini M, Bugliani M, Marchetti P, Cnop M, Eizirik DL, Fuks F (2012) DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J 31(6):1405–1426CrossRefGoogle Scholar
  59. Werling NJ, Thorpe R, Zhao Y (2013) A systematic approach to the establishment and characterization of endothelial progenitor cells for gene therapy. Hum Gene Ther Methods 24(3):171–184CrossRefGoogle Scholar
  60. Whitelaw NC, Whitelaw E (2008) Transgenerational epigenetic inheritance in health and disease. Curr Opin Genet Dev 18(3):273–279CrossRefGoogle Scholar
  61. Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG (2010) Evidence of increased islet cell proliferation in patients with recent-onset type 1 diabetes. Diabetologia 53(9):2020–2028CrossRefGoogle Scholar
  62. Williams KT, Garrow TA, Schalinske KL (2008) Type I diabetes leads to tissue-specific DNA hypomethylation in male rats. J Nutr 138(11):2064–2069CrossRefGoogle Scholar
  63. Yoon Y (2013) Reprogramming diabetic stem or progenitor cells for treating diabetic complications. Trans-NIH Angiogenesis Workshop, Division of Cancer Prevention. Lister Hill, NIH Main Campus, Division of Cancer PreventionGoogle Scholar
  64. Yuen RK, Jiang R, Penaherrera MS, McFadden DE, Robinson WP (2011) Genome-wide mapping of imprinted differentially methylated regions by DNA methylation profiling of human placentas from triploidies. Epigenetics Chromatin 4(1):10CrossRefGoogle Scholar
  65. Zhang H, Cai X, Yi B, Huang J, Wang J, Sun J (2014) Correlation of CTGF gene promoter methylation with CTGF expression in type 2 diabetes mellitus with or without nephropathy. Mol Med Rep 9(6):2138–2144CrossRefGoogle Scholar
  66. Zhao J, Goldberg J, Bremner JD, Vaccarino V (2012) Global DNA methylation is associated with insulin resistance: a monozygotic twin study. Diabetes 61(2):542–546CrossRefGoogle Scholar
  67. Zhong Q, Kowluru RA (2010) Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon. J Cell Biochem 110(6):1306–1313CrossRefGoogle Scholar
  68. Zuo GW, Kohls CD, He BC, Chen L, Zhang W, Shi Q, Zhang BQ, Kang Q, Luo J, Luo X, Wagner ER, Kim SH, Restegar F, Haydon RC, Deng ZL, Luu HH, He TC, Luo Q (2010) The CCN proteins: important signaling mediators in stem cell differentiation and tumorigenesis. Histol Histopathol 25(6):795–806PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Cell Biology and Anatomy, Chicago Medical SchoolRosalind Franklin University of Medicine and ScienceNorth ChicagoUSA
  2. 2.Division of Biomedical Statistics and InformaticsMayo ClinicRochesterUSA

Personalised recommendations