pericytes and SMCs are able to downregulate glucose uptake to protect themselves from hyperglycemic damage (113). It is thus speculated that pericytes take up AGEs from the circulation or from the direct vicinity suggesting a clearing function under specific conditions. Since the tissue load with AGEs changes over time in diabetes, the role of pericytes as AGE-removing cell compartment becomes increasingly relevant. However, the time course of AGE accumulation in pericytes (occurring over several months) is inconsistent with the time course of pericyte loss (starting after approximately 8 weeks of diabetes with a plateau after 6 months in diabetic animals), suggesting that AGEs may not be causally involved in incipient pericyte loss.

MODIFICATION OF LDL

Another piece of evidence suggests that pericytes may be injured by toxic plasma proteins which predominantly form in the diabetic milieu. Pericytes are differentially susceptible to damage by modified LDL in vitro (114). As in vivo correlate, the combination of elevated glucose and lipids in ApoE−/− db/db mice led to an almost doubling of pericyte ghosts after 6 months of exposure. The majority of genes upregulated in human pericytes exposed to modifications of LDL such as oxidized-glycated LDL belong to the families of signal transduction, enzymes, and lipid metabolism (115). One interesting gene regulated by exposure of pericytes to modified lipids is TIMP-3, which controls vessel stability and maturation in vitro (116). Exposure of cultured human retinal pericytes to glycatedoxidized LDL repressed TIMP-3 expression by 2.41 fold vs. pericytes exposed to unmodified LDL. Given the close cell-cell communication based on physical contacts between endothelial cells and pericytes, it is conceivable that the MMP-TIMP system can play a significant role in execution of vascular stabilization by pericytes, and to the respective alteration in diabetes (117). Although a clear clinical benefit of lipid-lowering treatment for diabetic retinopathy has not been demonstrated (118, 119), the preclinical data and evidence from associative studies suggest an association between lipoprotein profiles and the severity of retinopathy at least in type 1 diabetes (120). It must be kept in mind that lipid-lowering drugs can have an independent effect on pericyte survival. For instance, it was recently reported that statins, in particular simvastatin, a potent HMG-CoA reductase inhibitor, can selectively induce pericyte apoptosis in vitro.

Loss Through Active Elimination

Alternative to early pericyte loss in diabetic retinopathy being the result of hyperglycemic injury, a different concept was proposed. It is possible that pericyte loss is an active process involving migration of pericytes away from the capillaries, driven by the Angiopoietin-Tie system. As described, gain of function experiments in nondiabetic animals revealed the induction of pericyte dropout in the vicinity of the Ang-2 overexpressing site. Superimposition of diabetes aggravated the most important vascular readout, i.e., the formation of acellular capillaries. Loss of function studies in the presence of diabetes yielded the prevention of pericyte dropout and the reduction of acellular capillary formation. Ang-2 is expressed in three cell types of the retina, i.e., the endothelial cell, the Müller cells, and the horizontal cells. In situ hybridization of diabetic retinae with Ang-2 yielded the expression particularly in Müller cells. However, the regulation of Ang-2 in chronic hyperglycemia has not been understood until recently.

For a better understanding, a short summary of the biochemical state of the art is given.

As mentioned, four pathways have been investigated over many years to explain how diabetes can affect diabetic vascular target cells: the sorbitol pathway, the hexosamine pathway, and the protein kinase C pathway, and increased production of AGEs. Recently, these seemingly independent biochemical pathways have been linked by the findings that one single mechanism, hyperglycemia-induced mitochondrial overproduction of reactive oxygen species, is the underlying cause, which, mediated through the enzyme poly-ADP-ribose polymerase, blocks activities of the critical glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (121, 122). In normal cells, glucose is metabolized through glycolysis and the tricarbon cycle to generate electron donors for the mitochondrial respiratory chain. Here, energy (ATP) is generated in a precisely regulated way. In hyperglycemic cells, increased flux through glycolysis and the TCA cycle generates a voltage gradient of electrons surpassing a certain threshold which is then blocked inside complex III of the mitochondrial electron transport chain. From complex III, the surplus of electrons is purported to coenzyme Q together with molecular oxygen producing superoxide. The mitochondrial form of superoxide dismutase detoxifies this radical via hydrogen peroxide to water in the presence of oxygen. The link between the four biochemical pathways, and the mitochondrial overproduction of ROS was made, when it became evident that an important change in hyperglycemic cells and in experimental animals was the reduced activity of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase. When examining for biochemical modifications of the enzyme, it was observed that hyperglycemia-induced superoxides caused polymers of ADP ribose to attach and reduce enzyme activity. These changes were prevented with the inhibition of superoxide generation, and with the inhibition of the nuclear enzyme poly-ADP-ribose polymerase using a specific PARP inhibitor. The latter is activated upon DNA strand brakes known to form in hyperglycemic cells. Reduced GAPDH activity induced by PARP activation activates the biochemical pathways by increasing intermediates such as diacyl-glycerol (PKC pathway), glyceraldehyde-3- phosphate (AGE pathway), fructose-6-phosphate (hexosamine pathway), and intracellular glucose (sorbitol pathway). Thus, hyperglycemia links to biochemical pathway abnormalities via a common denominator, mitochondrial overproduction of reactive oxygen species. Methyglyoxal is the most important intracellular AGE precursor. Methylglyoxal-induced hydroimidazolones are the predominant modifications of intracellular proteins. They react with amino groups of arginine in intracellular proteins to form AGEs, which are detoxified by the glyoxalase system (123).

Methylglyoxal has been recently implicated in the mechanism of how high glucose regulates gene expression. It was found that increased glucose flux in renal microvascular endothelial cells caused increased modification of the corepressor mSin3A by methylglyoxal resulting in recruitment of the enzyme O-GlcNAc transferase to an mSin3A-Sp3complex.Subsequently,Sp3modificationbyO-linkedN-acetylglucosamine decreased its binding to a glucose-responsive GC box in the Ang-2 promoter and the activation of Ang-2 transcription (Fig. 3) (124). The same mechanism was operative in retinal Müller cells consistent with in vivo data from retinae of diabetic rats and mice. These data are consistent with the novel hypothesis, i.e., that pericyte loss is actively induced by glial cell overexpression Ang-2 in response to high glucose.

4.Etchevers, H.C., et al., The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development, 2001. 128(7): p. 1059–68.

5.Yamashita, J., et al., Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature, 2000. 408(6808): p. 92–6.

6.DeRuiter, M.C., et al., Embryonic endothelial cells transdifferentiate into mesenchymal cells expressing smooth muscle actins in vivo and in vitro. Circ Res, 1997. 80(4): p. 444–51.

7.Rajantie, I., et al., Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood, 2004. 104(7): p. 2084–6.

8.Caballero, S., et al., Ischemic vascular damage can be repaired by healthy, but not diabetic, endothelial progenitor cells. Diabetes, 2007. 56(4): p. 960–7.

9.van Deurs, B., Observations on the blood-brain barrier in hypertensive rats, with particular reference to phagocytic pericytes. J Ultrastruct Res, 1976. 56(1): p. 65–77.

10.Thomas, W.E., Brain macrophages: on the role of pericytes and perivascular cells. Brain Res Brain Res Rev, 1999. 31(1): p. 42–57.

11.Hirschi, K.K., S.A. Rohovsky, and P.A. D’Amore, PDGF, TGF-beta, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. J Cell Biol, 1998. 141(3): p. 805–14.

12.Nicosia, R.F., and S. Villaschi, Rat aortic smooth muscle cells become pericytes during angiogenesis in vitro. Lab Invest, 1995. 73(5): p. 658–66.

13.Villaschi, S., R.F. Nicosia, and M.R. Smith, Isolation of a morphologically and functionally distinct smooth muscle cell type from the intimal aspect of the normal rat aorta. Evidence for smooth muscle cell heterogeneity. In Vitro Cell Dev Biol Anim, 1994. 30A(9): p. 589–95.

14.Nehls, V., K. Denzer, and D. Drenckhahn, Pericyte involvement in capillary sprouting during angiogenesis in situ. Cell Tissue Res, 1992. 270(3): p. 469–74.

15.Sundberg, C., et al., Pericytes as collagen-producing cells in excessive dermal scarring. Lab Invest, 1996. 74(2): p. 452–66.

16.Farrington-Rock, C., et al., Chondrogenic and adipogenic potential of microvascular pericytes. Circulation, 2004. 110(15): p. 2226–32.

17.Schor, A.M., et al., Pericytes derived from the retinal microvasculature undergo calcification in vitro. J Cell Sci, 1990. 97 (Pt 3): p. 449–61.

18.Cogan, D.G., D. Toussaint, and T. Kuwabara, Retinal vascular patterns. IV. Diabetic retinopathy. Arch Ophthalmol, 1961. 66: p. 366–78.

19.Kuwabara, T., and D.G. Cogan, Retinal vascular patterns. VI. Mural cells of the retinal capillaries. Arch Ophthalmol, 1963. 69: p. 492–502.

20.Allt, G. and J.G. Lawrenson, Pericytes: cell biology and pathology. Cells Tissues Organs, 2001. 169(1): p. 1–11.

21.Sims, D.E., The pericyte–a review. Tissue Cell, 1986. 18(2): p. 153–74.

22.Sims, D.E., Recent advances in pericyte biology–implications for health and disease. Can J Cardiol, 1991. 7(10): p. 431–43.

23.Shepro, D. and N.M. Morel, Pericyte physiology. Faseb J, 1993. 7(11): p. 1031–8.

24.Tilton, R.G., et al., Pericyte degeneration and acellular capillaries are increased in the feet of human diabetic patients. Diabetologia, 1985. 28(12): p. 895–900.

25.Wakui, S., et al., Transforming growth factor-beta and urokinase plasminogen activator presents at endothelial cell-pericyte interdigitation in human granulation tissue. Microvasc Res, 1997. 54(3): p. 262–9.

26.Armulik, A., A. Abramsson, and C.Betsholtz, Endothelial/Pericyte Interactions. Circ Res, 2005. 97(6): p. 512–23.

27.Gerhardt, H. and C. Betsholtz, Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res, 2003. 314(1): p. 15–23.

28.Larson, D.M., M.P. Carson, and C.C. Haudenschild, Junctional transfer of small molecules in cultured bovine brain microvascular endothelial cells and pericytes. Microvasc Res, 1987. 34(2): p. 184–99.

29.Crocker, D.J., T.M. Murad, and J.C.Geer, Role of the pericyte in wound healing: an ultrastructural study. Exp Mol Pathol, 1970. 13(1): p. 51–65.

30.Fujimoto, K., Pericyte-endothelial gap junctions in developing rat cerebral capillaries: a fine structural study. Anat Rec, 1995. 242(4): p. 562–5.

31.Hori, S., et al., A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro. J Neurochem, 2004. 89(2):

p.503–13.

32.Courtoy, P.J. , and J. Boyles, Fibronectin in the microvasculature: localization in the pericyte-endothe- lial interstitium. J Ultrastruct Res, 1983. 83(3): p. 258–73.

33.Hirschi, K.K. and P.A. D’Amore, Pericytes in the microvasculature. Cardiovasc Res, 1996. 32(4):

p.687–98.

34.Rucker, H.K., H.J. Wynder, and W.E. Thomas, Cellular mechanisms of CNS pericytes. Brain Res Bull, 2000. 51(5): p. 363–69.

35.Bondjers, C., et al., Transcription profiling of platelet-derived growth factor-B-deficient mouse embryos identifies RGS5 as a novel marker for pericytes and vascular smooth muscle cells. Am J Pathol, 2003. 162(3): p. 721–9.

36.Cho, H., et al., Pericyte-specific expression of Rgs5: implications for PDGF and EDG receptor signaling during vascular maturation. Faseb J, 2003. 17(3): p. 440–2.

37.Joyce, N.C., et al., cGMP-dependent protein kinase is present in high concentrations in contractile cells of the kidney vasculature. J Cyclic Nucleotide Protein Phosphor Res, 1986. 11(3): p. 191–8.

38.Lindahl, P., et al., Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science, 1997. 277(5323): p. 242–5.

39.Nehls, V. and D. Drenckhahn, Heterogeneity of microvascular pericytes for smooth muscle type alpha-actin. J Cell Biol, 1991. 113(1): p. 147–54.

40.Ozerdem, U., et al., NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev Dyn, 2001. 222(2): p. 218–27.

41.Piva, T.J., D.R. Krause, and K.O. Ellem, UVC activation of the HeLa cell membrane “TGF alpha ase,” a metalloenzyme. J Cell Biochem, 1997. 64(3): p. 353–68.

42.Ruiter, D.J., et al., Angiogenesis in wound healing and tumor metastasis. Behring Inst Mitt, 1993(92):

p.258–72.

43.Tidhar, A., et al., A novel transgenic marker for migrating limb muscle precursors and for vascular smooth muscle cells. Dev Dyn, 2001. 220(1): p. 60–73.

44.Song, S., et al., PDGFRbeta + perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol, 2005. 7(9): p. 870–9.

45.Bondjers, C., et al., Microarray analysis of blood microvessels from PDGF-B and PDGF-R{beta} mutant mice identifies novel markers for brain pericytes. FASEB J., 2006. 20(10): p. 1703–5.

46.Bergers, G. and S. Song, The role of pericytes in blood-vessel formation and maintenance. Neurooncol, 2005. 7(4): p. 452–64.

47.Joyce, N.C., M.F. Haire, and G.E. Palade, Contractile proteins in pericytes. II. Immunocytochemical evidence for the presence of two isomyosins in graded concentrations. J Cell Biol, 1985. 100(5): p. 1387–95.

48.Joyce, N.C., M.F. Haire, and G.E. Palade, Contractile proteins in pericytes. I. Immunoperoxidase localization of tropomyosin. J. Cell Biol, 1985. 100(5): p. 1379–86.

49.Peppiatt, C.M., et al., Bidirectional control of CNS capillary diameter by pericytes. Nature, 2006. 443(7112): p. 700–4.

50.Bauer, H.C., M. Steiner, and H. Bauer, Embryonic development of the CNS microvasculature in the mouse: new insights into the structural mechanisms of early angiogenesis. Exs, 1992. 61: p. 64–8.

51.Gerhardt, H., H. Wolburg, and C. Redies, N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev Dyn, 2000. 218(3): p. 472–9.

52.Egginton, S., et al., The role of pericytes in controlling angiogenesis in vivo. Adv Exp Med Biol, 2000. 476: p. 81–99.

53.Balabanov, R. and P. Dore-Duffy, Role of the CNS microvascular pericyte in the blood-brain barrier. J Neurosci Res, 1998. 53(6): p. 637–44.

54.Wakui, S., et al., Localization of Ang-1, -2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis. Lab Invest, 2006. 86(11): p. 1172–84.

55.Uemura, A., et al., Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells. J Clin Invest, 2002. 110(11): p. 1619–28.

56.Carmeliet, P., Mechanisms of angiogenesis and arteriogenesis. Nat Med, 2000. 6(4): p. 389–95.

57.Yancopoulos, G.D., et al., Vascular-specific growth factors and blood vessel formation. Nature, 2000. 407(6801): p. 242–8.

58.Gerhardt, H., et al., VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol, 2003. 161(6): p. 1163–77.

59.Anderson, C.R., A.M. Ponce, and R.J. Price, Immunohistochemical identification of an extracellular matrix scaffold that microguides capillary sprouting in vivo. J Histochem Cytochem, 2004. 52(8): p. 1063–72.

60.Betsholtz, C., Insight into the physiological functions of PDGF through genetic studies in mice. Cytokine Growth Factor Rev, 2004. 15(4): p. 215–28.

61.Jain, R.K., Molecular regulation of vessel maturation. Nat Med, 2003. 9(6): p. 685–93.

62.Weinstein, M., X. Yang, and C. Deng, Functions of mammalian Smad genes as revealed by targeted gene disruption in mice. Cytokine Growth Factor Rev, 2000. 11(1–2): p. 49–58.

63.Benjamin, L.E., I. Hemo, and E. Keshet, A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development, 1998. 125(9): p. 1591–8.

64.Ozerdem, U. and W.B. Stallcup, Early contribution of pericytes to angiogenic sprouting and tube formation. Angiogenesis, 2003. 6(3): p. 241–9.

65.Cohen, M.P., R.N. Frank, and A.A. Khalifa, Collagen production by cultured retinal capillary pericytes. Invest Ophthalmol Vis Sci, 1980. 19(1): p. 90–4.

66.Weibel, E.R., On pericytes, particularly their existence on lung capillaries. Microvasc Res, 1974. 8(2): p. 218–35.

67.Schor, A.M., et al., Differentiation of pericytes in culture is accompanied by changes in the extracellular matrix. In Vitro Cell Dev Biol, 1991. 27A(8): p. 651–9.

68.Kennedy, A., R.N. Frank, and M.A. Mancini, In vitro production of glycosaminoglycans by retinal microvessel cells and lens epithelium. Invest. Ophthalmol. Vis. Sci., 1986. 27(5): p. 746–54.

69.Folkman, J. and P.A. D’Amore, Blood Vessel Formation: what is its molecular basis? Cell, 1996. 87(7): p. 1153–55.

70.Lindahl, P., et al., Endothelial-perivascular cell signaling in vascular development: lessons from knockout mice. Curr Opin Lipidol, 1998. 9(5): p. 407–11.

71.Orlidge, A. and P.A. D’Amore, Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells. J Cell Biol, 1987. 105(3): p. 1455–62.

72.Korff, T., et al., Blood vessel maturation in a 3-dimensional spheroidal coculture model: direct contact with smooth muscle cells regulates endothelial cell quiescence and abrogates VEGF responsiveness. Faseb J, 2001. 15(2): p. 447–57.

73.Sundberg, C., et al., Stable expression of angiopoietin-1 and other markers by cultured pericytes: phenotypic similarities to a subpopulation of cells in maturing vessels during later stages of angiogenesis in vivo. Lab Invest, 2002. 82(4): p. 387–401.

74.Hammes, H.P., et al., Aminoguanidine does not inhibit the initial phase of experimental diabetic retinopathy in rats. Diabetologia, 1995. 38(3): p. 269–73.

75.Kern, T.S., M.C. Tang J, and Du Y. , Differences among rat strains in the rate Eof development of early stages of diabetic retinopathy. Diabetes, 2006. 55 (S1)(A53).

76.Hoffmann, J., et al., Tenilsetam prevents early diabetic retinopathy without correcting pericyte loss. Thromb Haemost, 2006. 95(4): p. 689–95.

77.Lin, J., et al., Effect of R-(+)-alpha-lipoic acid on experimental diabetic retinopathy. Diabetologia, 2006. 49(5): p. 1089–96.

78.Robison, W.G., Jr., et al., Degenerated intramural pericytes (‘ghost cells’) in the retinal capillaries of diabetic rats. Curr Eye Res, 1991. 10(4): p. 339–50.

79.Papachristodoulou, D., H. Heath, and S.S. Kang, The development of retinopathy in sucrose-fed and streptozotocin-diabetic rats. Diabetologia, 1976. 12(4): p. 367–74.

80.Sima, A.A.F., R. Garcia-Salinas, and P.K. Basu, The BB Wistar rat: an experimental model for the study of diabetic retinopathy. Metabolism, 1983. 32(7, Supplement 1): p. 136–40.

81.Kakehashi, A., Y. Saito, K. Mori, N. Sugi, R. Ono, H. Yamagami, M. Shinohara, H. Tamemoto, S.E. Ishikawa, M. Kawakami, and Y. Kanazawa. Characteristics of diabetic retinopathy in SDR rats. Diabetes Metab Res Rev. 2006. Nov-Dec; 22(6):455–61.

82.Enge, M., et al., Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. Embo J, 2002. 21(16): p. 4307–16.

83.Agardh, C.D., et al., Altered endothelial/pericyte ratio in Goto-Kakizaki rat retina. J Diabetes Complicat, 1997. 11(3): p. 158–62.

84.Dosso, A., et al., Ocular complications in the old and glucose-intolerant genetically obese (fa/fa) rat. Diabetologia, 1990. 33(3): p. 137–44.

85.Kim, S.H., et al., Morphologic studies of the retina in a new diabetic model; SHR/N:Mcc-cp rat. Yonsei Med J, 1998. 39(5): p. 453–62.

86.Feit-Leichman, R.A., et al., Vascular damage in a mouse model of diabetic retinopathy: relation to neuronal and glial changes. Invest Ophthalmol Vis Sci, 2005. 46(11): p. 4281–7.

87.Barber, A.J., et al., The Ins2Akita Mouse as a Model of Early Retinal Complications in Diabetes. Invest Ophthalmol Vis Sci, 2005. 46(6): p. 2210–18.

88.Midena, E., et al., Studies on the retina of the diabetic db/db mouse. I. Endothelial cell-pericyte ratio. Ophthalmic Res, 1989. 21(2): p. 106–11.

89.Obrosova, I.G., et al., Early diabetes-induced biochemical changes in the retina: comparison of rat and mouse models. Diabetologia, 2006. 49(10): p. 2525–33.

90.Hammes, H.P., et al., The relationship of glycaemic level to advanced glycation end-product (AGE) accumulation and retinal pathology in the spontaneous diabetic hamster. Diabetologia, 1998. 41(2):

p.165–70.

91.Engerman, R.L. and T.S. Kern, Experimental galactosemia produces diabetic-like retinopathy. Diabetes, 1984. 33(1): p. 97–100.

92.Engerman, R.L. and T.S. Kern, Retinopathy in galactosemic dogs continues to progress after cessation of galactosemia. Arch Ophthalmol, 1995. 113(3): p. 355–8.

93.Engerman, R.L. and J.W. Kramer, Dogs with induced or spontaneous diabetes as models for the study of human diabetes mellitus. Diabetes, 1982. 31(Suppl 1 Pt 2): p. 26–9.

94.Kern, T.S. and R.L. Engerman, Vascular lesions in diabetes are distributed non-uniformly within the retina. Exp Eye Res, 1995. 60(5): p. 545–9.

95.Gardiner, T.A., et al., Selective loss of vascular smooth muscle cells in the retinal microcirculation of diabetic dogs. Br J Ophthalmol, 1994. 78(1): p. 54–60.

96.Kim, S.Y., et al., Retinopathy in Monkeys with Spontaneous Type 2 Diabetes. Invest Ophthalmol Vis Sci, 2004. 45(12): p. 4543–53.

97.Buchi, E.R., A. Kurosawa, and M.O. Tso, Retinopathy in diabetic hypertensive monkeys: a pathologic study. Graefes Arch Clin Exp Ophthalmol, 1996. 234(6): p. 388–98.

98.Lindahl, P., et al., Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science, 1997. 277(5323): p. 242–5.

99.Hammes, H.P., et al., Pericytes and the pathogenesis of diabetic retinopathy. Diabetes, 2002. 51(10):

p.3107–12.

100.Asahara, T., et al., Tie2 Receptor Ligands, Angiopoietin-1 and Angiopoietin-2, Modulate VEGFInduced Postnatal Neovascularization. Circ Res, 1998. 83(3): p. 233–40.

101.Hammes, H.P., et al., Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. Diabetes, 2004. 53(4): p. 1104–10.

102.Feng, Y., et al., Impaired pericyte recruitment and abnormal retinal angiogenesis as a result of angio- poietin-2 overexpression. Thromb Haemost, 2007. 97(1): p. 99–108.

103.Stalmans, I., et al., Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest, 2002. 109(3): p. 327–36.

104.Ruberte, J., et al., Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease. J Clin Invest, 2004. 113(8): p. 1149–57.

105.Kowluru, R.A. and S. Odenbach, Effect of long-term administration of alpha-lipoic acid on retinal capillary cell death and the development of retinopathy in diabetic rats. Diabetes, 2004. 53(12):

p.3233–8.

106.Mizutani, M., T.S. Kern, and M. Lorenzi, Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest, 1996. 97(12): p. 2883–90.

107.Akagi, Y., et al., Aldose reductase localization in human retinal mural cells. Invest Ophthalmol Vis Sci, 1983. 24(11): p. 1516–19.

108.Berrone, E., et al., Regulation of intracellular glucose and polyol pathway by thiamine and benfotiamine in vascular cells cultured in high glucose. J Biol Chem, 2006. 281(14): p. 9307–13.

109.Yamagishi, S., et al., Advanced glycation endproducts accelerate calcification in microvascular pericytes. Biochem Biophys Res Commun, 1999. 258(2): p. 353–7.

110.Stitt, A.W., et al., Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. Am J Pathol, 1997. 150(2): p. 523–31.

111.Xu, X., et al., Exogenous advanced glycosylation end products induce diabetes-like vascular dysfunction in normal rats: a factor in diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol, 2003. 241(1): p. 56–62.

112.Yamagishi, S.-I., et al., Advanced Glycation Endproducts Accelerate Calcification in Microvascular Pericytes. Biochem Biophys Res Commun, 1999. 258(2): p. 353–7.

113.Kaiser, N., et al., Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. Diabetes, 1993. 42(1): p. 80–9.

114.Lyons, T.J., et al., Aminoguanidine and the Effects of Modified LDL on Cultured Retinal Capillary Cells. Invest Ophthalmol Vis Sci, 2000. 41(5): p. 1176–80.

115.Song, W., et al., Effects of oxidized and glycated ldl on gene expression in human retinal capillary pericytes. Invest Ophthalmol Vis Sci, 2005. 46(8): p. 2974–82.

116.Davis, G.E. and W.B. Saunders, Molecular balance of capillary tube formation versus regression in wound repair: role of matrix metalloproteinases and their inhibitors. J Investig Dermatol Symp Proc, 2006. 11(1): p. 44–56.

117.Barth, J.L., et al., Oxidised, glycated LDL selectively influences tissue inhibitor of metalloprotei- nase-3 gene expression and protein production in human retinal capillary pericytes. Diabetologia, 2007. 50(10): p. 2200–8.

118.Keech, A., R.J. Simes, P. Barter, J. Best, R. Scott, M.R. Taskinen, P. Forder, A. Pillai, T. Davis, P. Glasziou, P. Drury, Y.A. Kesäniemi, D. Sullivan, D. Hunt, P. Colman, M. d’Emden, M. Whiting, C. Ehnholm, and M. Laakso. FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005 Nov 26;366(9500): 1849–61.

119.Colhoun, H.M., et al., Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-con- trolled trial. The Lancet. 364(9435): p. 685–96.

120.Lyons, T.J., et al., Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci, 2004. 45(3): p. 910–8.

121.Brownlee, M., Biochemistry and molecular cell biology of diabetic complications. Nature, 2001. 414(6865): p. 813–20.

122.Hammes, H.-P., Pathophysiological mechanisms of diabetic angiopathy. J Diabetes Complicat, 2003. 17(2, Supplement 1): p. 16–19.

123.Abordo, E.A., H.S. Minhas, and P.J. Thornalley, Accumulation of [alpha]-oxoaldehydes during oxidative stress: a role in cytotoxicity. Biochem Pharmacol, 1999. 58(4): p. 641–48.

124.Yao, D., et al., High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A. J Biol Chem, 2007. 282(42): p. 31038–45.

125.Pfister, F., Y. Feng, F. Vom Hagen, S. Hoffmann, G. Molema, J.L. Hillebrands, M. Shani, U. Deutsch, H.P. Hammes. Pericyte migration: A novel mechanism of pericyte loss in experimental diabetic retinopathy. Diabetes. 2008 Jun 16. [Epub ahed of print]