help button home button Am J Pathol ASIP WHAT IS IT?
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

This Article
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Benjamin, L. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Benjamin, L. E.
(American Journal of Pathology. 2001;158:1181-1184.)
© 2001 American Society for Investigative Pathology

Commentaries

Glucose, VEGF-A, and Diabetic Complications

Laura E. Benjamin

From the Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston Massachusetts

Diabetes is a widespread disease with multiple complications that affect both the microvasculature and macrovasculature. In the past decade, studies of the underlying factors in diabetic complications have resulted in an interesting dilemma: both microvascular insufficiencies and microvascular proliferative diseases plague diabetic patients, sometimes simultaneously. Advances in therapeutic treatments of microvascular disease continue to show promise for the treatment of the variety of diabetic complications. Although many factors have been shown to contribute to these complications, the angiogenic growth and survival factor, vascular endothelial growth factor (VEGF)-A, is commonly mis-regulated in most microvascular disorders. The short communication by Pinter and colleagues1 found in this issue of The American Journal of Pathology demonstrates this correlation yet another time, only for the first time these authors investigate the effects of hyperglycemia on VEGF-A function during embryonic vascular development.

One of the more studied microvascular complications in diabetes is proliferative retinopathy. The large number of studies regarding etiology and treatment of this blindness-causing disease have shown that during proliferative stages, plasma and vitreous levels of VEGF-A are high in patients.2-7 Additionally, in specimens of diabetic retinas increased expression of VEGF-A and its three receptors has been extensively demonstrated.8-10 Other growth factors, such as IGF-1 and its receptor, have been shown to collaborate with VEGF-A to increase retinal neovascularization.11 Additionally, a study of diabetic patients that did not develop retinopathy showed that there was a correlation to impaired hypoxic induction of VEGF-A in these patients, again supporting the hypothesis that retinopathy involves hypoxic expression of VEGF-A as a fundamental aspect of its etiology.12 And importantly, antagonists of VEGF and its receptors have been shown to reduce retinopathy in animal models.13-16 VEGF-A function to induce permeability is also a likely contributor to the vascular leakage that greatly contributes to the morbidity of diabetic retinopathy.17,18

Other complications that have seen more progress in clinical studies are peripheral ischemia, marked by decreased microvascular function and subsequent circulation in the extremities, and neuropathy. Many diabetic patients suffer from both loss of circulation and neuropathy. The loss of feeling in their lower extremities further increases the likelihood of permanent tissue damage because of injury, and the poor circulation compromises wound healing and successful treatment of infections. Clinical trials to increase peripheral circulation by administering VEGF-A in one form or another have shown success in both increasing the circulation and reducing neuropathy.19-22 In particular, animal models of diabetes were examined for their response to injury and VEGF-A therapy in models of hindlimb ischemia. It was found that the severity of ischemia was increased in NOD (nonobese diabetic) mice, and this could be reduced by VEGF-A treatment.23 Samii and colleagues24 hypothesized that peripheral nerves and dorsal root ganglia in diabetic animals up-regulate VEGF-A and made the hypothesis that VEGF-A may help restore nerve function. Another less direct correlation could relate to the spatial co-ordination of the vascular and nervous system. This coordination may reflect a dependence of the nerves on the factors supplied via close proximity to blood vessels, and microvascular damage starves the nearby nerves.

Another major complication of diabetes is renal dysfunction. Recently some attention has been paid to the possible involvement of VEGF-A in this pathology. In streptozotocin-induced diabetic rats, VEGF-A and its receptor, VEGFR-2, were up-regulated in the kidney after 3 weeks, but not after 32 weeks.25 The transient increase seemed to be via VEGFR-2 expression in the glomerulus and may explain some of the renal changes in diabetic patients via VEGF-A permeability functions. VEGF-A-induced permeability alterations in the glomerulus could lead to the protein leakage into the urine of diabetic patients. Studies have shown that glucose-induced albumin permeation can be blocked by antagonism of VEGF-A function.26,27

The study presented in this issue of The American Journal of Pathology by Pinter and colleagues1 adds to the understanding of VEGF-A’s involvement in yet another complication of diabetes, that of vascular abnormalities in the embryos and fetuses of diabetic mothers.28 Fetuses of diabetic mothers have increased incidence of vascular abnormalities, some of which are diagnosed at birth and others are found after miscarriage or stillbirths.29,30 Moreover, earlier abnormalities may account for the increased fetal resorption and difficulty in establishing pregnancy.29,31-35 Pinter and colleagues1 established an embryo culture system that mimics the plasma glucose levels of diabetic mothers and diabetic animals and found that these embryos had malformations in the earliest vascular beds resulting in arrested development. They looked at VEGF-A expression in two ways. First they used a LacZ knock-in construct that eliminates the 3'UTR and inserts an internal ribosome entry site LacZ after the VEGF stop codon.36 In the heterozygous state this knock-in was fully viable and had a normal vasculature despite missing 50% of RNAs ability to respond to stabilization via the 3'UTR. In these animals, LacZ expression is a mark of VEGF-A transcription. Additionally, the authors looked at total VEGF-A protein on Western blots and observed that VEGF expression was reduced. In correlation with reduced VEGF expression, VEGF receptor signaling was reduced. The effects on VEGF-A signaling and the embryonic vasculopathy were eliminated by low levels of exogenous VEGF-A165 added to the culture medium. This result may be directly correlated to VEGFR-2 signaling because the related growth factor, PlGF, could not rescue these embryos. PlGF binds only to VEGR-1 and neuropilin, and thus partially distinguishes between VEGF receptor signaling.37-42

A large literature on the regulation of VEGF-A has demonstrated that VEGF-A levels are exquisitely sensitive to multiple ischemic agents, including oxygen, iron, and glucose.43-47 This regulation exists at multiple levels: 1)ischemia increases VEGF-A mRNA stability, in part via sequences in the 3'UTR and in association with the von Hippel Lindau protein.48,49 2) Ischemia increases transcription via hypoxia-inducible transcription factors.50 Null animals in one of the hypoxia-inducible transcription factors, ARNT, make less hypoxia-induced VEGF-A and die with vascular anomalies in the yolk sac similar to those of the VEGF-A knock-out and hyperglycemic embryos.51,52 3) Ischemia increases translation efficiency via an endogenous internal ribosome entry site.53 On the counter side, increased oxygen (hyperoxia)54-57 and increased glucose (hyperglycemia)58,59 have both been shown to reduce VEGF-A RNA levels, likely via the same mechanisms of RNA stability and transcription. Under the hyperglycemic conditions of the embryos cultured as reported by Pinter and colleagues,1 it is unclear whether VEGF-A levels are reduced via VEGF-A mRNA stability and transcriptional reductions. However, in their experiments using a LacZ reporter knock-in to the VEGF-A 3'UTR, at least the mRNA stability reported in association with that sequence (and interacting von Hippel Lindau protein) was nonfunctional suggesting that the LacZ expression changes seen in hyperglycemic cultures were transcriptional.

The regulation of VEGF-A by glucose has not been as extensively investigated as the oxygen regulation, but elegant studies of VEGF-A RNA expression in spheroids clearly demonstrated a similar regulation by hypoglycemia as hypoxia.45 In vitro experiments supporting this glucose regulation have been performed on tumor cells, glial cells, retinal Muller cells, and vascular smooth muscle cells.58-62 Moreover, similar to hypoglycemia, in vitro, acute insulin treatment induced VEGF-A expression.63 Insulin has also been reported to regulate transcription via the hypoxia-inducible transcription factors.64 One report suggesting a contrary effect of glucose on VEGF-A is specific to mesangial cells of the kidney.65 These studies suggested that hyperglycemia induced, rather than reduced VEGF-A expression. Should this result be correct in vivo, it would suggest that hyperglycemic incidents would transiently increase VEGF-A specifically in the kidney. In this organ such a response would lead to increased permeability in the glomerulus, a common symptom of diabetes.

Can glucose regulation of VEGF-A explain all of the microvascular complications in diabetes? The results of the 10-year diabetes control and complications trial conducted by the National Institute of Diabetes and Digestive and Kidney diseases showed that intensive treatment aimed at keeping blood sugar levels as close to normal as possible significantly reduced the onset and progression of retinopathy, nephropathy, and neuropathy.66 Thus it seems that oscillations in glucose should be kept to a minimum. It may be that low glucose (high VEGF-A) levels can account for both sporadic proliferative events (such as retinopathy); and high glucose levels (low VEGF-A) can account for microvascular insufficiencies (loss of microvessels). It was widely believed that VEGF-A fluctuations in a stable and mature vasculature could not cause alterations in the vasculature without pre-existing vascular injury to allow greater responsiveness to VEGF-A. However, recent studies reporting the administration of adenovirus expressing VEGF-A to a fully mature vascular bed demonstrated massive vascular proliferation and associated edema.67 Whether decreased VEGF-A in an adult vascular bed can lead to regression has not been clearly established. Nonetheless, it seems that increased VEGF-A in diabetic patients because of too much insulin, for example, could initiate a proliferative situation accompanied by edema and set off the initial vascular instabilities that are then more sensitive to further glucose/VEGF-A fluctuations. Thus, in the same patient episodic gross fluctuations can either lead to microvascular proliferation or loss. As for macrovascular complications of diabetes, these may be partially independent of the microvascular,68 but it is clear that these complications and their treatments are made more complex in diabetic patients because of suboptimal microvascular function.

One potential problem for the diabetic patient that has not been solved is how to treat one vascular complication without exacerbating another. For retinopathy decreased angiogenesis is desired, whereas for peripheral ischemia increased angiogenesis is desired. For example, would a systemic treatment for peripheral ischemia designed to stimulate microvessel proliferation aggravate proliferative retinopathy? Or vice versa, would VEGF-A antagonists designed to treat retinopathy accelerate the onset of cardiovascular or peripheral vascular disease? To date very little has been done to determine the answer to such questions. One difficulty in addressing this issue is the paucity of diabetic animal models that acquire multiple complications the way humans do. Unlike the current anti-angiogenic treatments in clinical trials for cancer, treatment of diabetic vascular diseases may need to be organ-specific. Thus it seems likely that alternate treatments for vascular disease that are either local or independent of systemic factors such as VEGF-A are needed to maintain a healthy balance in diabetic patients with multiple complications.

Footnotes

Address reprint requests to Laura E. Benjamin, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston MA 02215. E-mail: lbenjami{at}caregroup.harvard.edu

Supported by a research grant from the American Diabetes Association.

Accepted for publication February 2, 2001.

References

  1. Pinter E, Haigh J, Nagy A, Madri J: Hyperglycemia-induced vasculopathy in the murine conceptus is mediated via reductions of VEGF-A expression and VEGF receptor activation. Am J Pathol 2001, 158:1199-1206[Abstract/Free Full Text]
  2. Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, Nguyen HV, Aiello LM, Ferrara N, King GL: Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994, 331:1480-1487[Abstract/Free Full Text]
  3. Adamis AP, Miller JW, Bernal MT, D’Amico DJ, Folkman J, Yeo TK, Yeo KT: Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol 1994, 118:445-450[Medline]
  4. Boulton M, Foreman D, Williams G, McLeod D: VEGF localisation in diabetic retinopathy. Br J Ophthalmol 1998, 82:561-568[Abstract/Free Full Text]
  5. Burgos R, Simo R, Audi L, Mateo C, Mesa J, Garcia-Ramirez M, Carrascosa A: Vitreous levels of vascular endothelial growth factor are not influenced by its serum concentrations in diabetic retinopathy. Diabetologia 1997, 40:1107-1109[Medline]
  6. Katsura Y, Okano T, Noritake M, Kosano H, Nishigori H, Kado S, Matsuoka T: Hepatocyte growth factor in vitreous fluid of patients with proliferative diabetic retinopathy and other retinal disorders. Diabetes Care 1998, 21:1759-1763[Abstract]
  7. Pe’er J, Folberg R, Itin A, Gnessin H, Hemo I, Keshet E: Upregulated expression of vascular endothelial growth factor in proliferative diabetic retinopathy. Br J Ophthalmol 1996, 80:241-245[Abstract/Free Full Text]
  8. Lip PL, Belgore F, Blann AD, Hope-Ross MW, Gibson JM, Lip GY: Plasma VEGF and soluble VEGF receptor FLT-1 in proliferative retinopathy: relationship to endothelial dysfunction and laser treatment. Invest Ophthalmol Vis Sci 2000, 41:2115-2119[Abstract/Free Full Text]
  9. Ishida S, Shinoda K, Kawashima S, Oguchi Y, Okada Y, Ikeda E: Coexpression of VEGF receptors VEGF-R2 and neuropilin-1 in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 2000, 41:1649-1656[Abstract/Free Full Text]
  10. Smith G, McLeod D, Foreman D, Boulton M: Immunolocalisation of the VEGF receptors FLT-1, KDR, and FLT-4 in diabetic retinopathy. Br J Ophthalmol 1999, 83:486-494[Abstract/Free Full Text]
  11. Smith LE, Shen W, Perruzzi C, Soker S, Kinose F, Xu X, Robinson G, Driver S, Bischoff J, Zhang B, Schaeffer JM, Senger DR: Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor. Nat Med 1999, 5:1390-1395[Medline]
  12. Marsh S, Nakhoul FM, Skorecki K, Rubin A, Miller BP, Leibu R, Levy NS, Levy AP: Hypoxic induction of vascular endothelial growth factor is markedly decreased in diabetic individuals who do not develop retinopathy. Diabetes Care 2000, 23:1375-1380[Abstract/Free Full Text]
  13. Ozaki H, Seo MS, Ozaki K, Yamada H, Yamada E, Okamoto N, Hofmann F, Wood JM, Campochiaro PA: Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization. Am J Pathol 2000, 156:697-707[Abstract/Free Full Text]
  14. Smith LE, Wesolowski E, McLellan A, Kostyk SK, D’Amato R, Sullivan R, D’Amore PA: Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci 1994, 35:101-111[Abstract/Free Full Text]
  15. Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L, Ferrara N, King GL, Smith LE: Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA 1995, 92:10457-10461[Abstract/Free Full Text]
  16. Robinson GS, Pierce EA, Rook SL, Foley E, Webb R, Smith LE: Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy. Proc Natl Acad Sci USA 1996, 93:4851-4856[Abstract/Free Full Text]
  17. Aiello LP, Bursell SE, Clermont A, Duh E, Ishii H, Takagi C, Mori F, Ciulla TA, Ways K, Jirousek M, Smith LE, King GL: Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997, 46:1473-1480[Abstract]
  18. Murata T, Ishibashi T, Khalil A, Hata Y, Yoshikawa H, Inomata H: Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels. Ophthalmic Res 1995, 27:48-52[Medline]
  19. Tsurumi Y, Takeshita S, Chen D, Kearney M, Rossow ST, Passeri J, Horowitz JR, Symes JF, Isner JM: Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion. Circulation 1996, 94:3281-3290[Abstract/Free Full Text]
  20. Isner JM, Walsh K, Symes J, Pieczek A, Takeshita S, Lowry J, Rosenfield K, Weir L, Brogi E, Jurayj D: Arterial gene transfer for therapeutic angiogenesis in patients with peripheral artery disease. Hum Gene Ther 1996, 7:959-988[Medline]
  21. Baumgartner I, Pieczek A, Manor O, Blair R, Kearney M, Walsh K, Isner JM: Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998, 97:1114-1123[Abstract/Free Full Text]
  22. Baumgartner I, Isner JM: Stimulation of peripheral angiogenesis by vascular endothelial growth factor (VEGF). Vasa 1998, 27:201-206[Medline]
  23. Rivard A, Silver M, Chen D, Kearney M, Magner M, Annex B, Peters K, Isner JM: Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am J Pathol 1999, 154:355-363[Abstract/Free Full Text]
  24. Samii A, Unger J, Lange W: Vascular endothelial growth factor expression in peripheral nerves and dorsal root ganglia in diabetic neuropathy in rats. Neurosci Lett 1999, 262:159-162[Medline]
  25. Cooper ME, Vranes D, Youssef S, Stacker SA, Cox AJ, Rizkalla B, Casley DJ, Bach LA, Kelly DJ, Gilbert RE: Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes 1999, 48:2229-2239[Abstract]
  26. Tilton RG, Kawamura T, Chang KC, Ido Y, Bjercke RJ, Stephan CC, Brock TA, Williamson JR: Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor. J Clin Invest 1997, 99:2192-2202[Medline]
  27. Stephan CC, Chang KC, LeJeune W, Erichsen D, Bjercke RJ, Rege A, Biediger RJ, Kogan TP, Brock TA, Williamson JR, Tilton RG: Role for heparin-binding growth factors in glucose-induced vascular dysfunction. Diabetes 1998, 47:1771-1778[Abstract]
  28. Ferencz C, Rubin JD, McCarter RJ, Clark EB: Maternal diabetes and cardiovascular malformations: predominance of double outlet right ventricle and truncus arteriosus. Teratology 1990, 41:319-326[Medline]
  29. Eriksson UJ, Borg LA, Forsberg H, Styrud J: Diabetic embryopathy. Studies with animal and in vitro models. Diabetes 1991, 40(Suppl 2):94-98
  30. Kitzmiller JL, Buchanan TA, Kjos S, Combs CA, Ratner RE: Pre-conception care of diabetes, congenital malformations, and spontaneous abortions. Diabetes Care 1996, 19:514-541[Medline]
  31. Schwarz R, Teramo KA: Effects of diabetic retinopathy on the fetus and newborn. Semin Perinatol 2000, 24:120-135[Medline]
  32. Lee AT, Plump A, DeSimone C, Cerami A, Bucala R: A role for DNA mutations in diabetes-associated teratogenesis in transgenic embryos. Diabetes 1995, 44:20-24[Abstract]
  33. Baker L, Piddlington R: Diabetic embryopathy: a selective review of recent trends. J Diabetes Comp 1993, 7:404-412
  34. Pampfer S, Vanderheyden I, MacCracken JE, Vesela J, DeHertogh R: Increased cell death in rat blastocysts exposed to maternal diabetes in utero and to high glucose of tumor necrosis factor {alpha} in vitro. Development 1997, 124:4827-4836[Abstract]
  35. Ellington SK: Effects of excess glucose on mammalian post-implantation embryos. Int J Dev Biol 1997, 41:299-306[Medline]
  36. Miquerol L, Langille BL, Nagy A: Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. Development 2000, 127:3941-3946[Abstract]
  37. DiSalvo J, Bayne ML, Conn G, Kwok PW, Trivedi PG, Soderman DD, Palisi TM, Sullivan KA, Thomas KA: Purification and characterization of a naturally occurring vascular endothelial growth factor: placenta growth factor heterodimer. J Biol Chem 1995, 270:7717-7723[Abstract/Free Full Text]
  38. Park JE, Chen HH, Winer J, Houck KA, Ferrara N: Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 1994, 269:25646-25654[Abstract/Free Full Text]
  39. Maglione D, Guerriero V, Viglietto G, Delli-Bovi P, Persico MG: Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci USA 1991, 88:9267-9271[Abstract/Free Full Text]
  40. Kawasaki T, Kitsukawa T, Bekku Y, Matsuda Y, Sanbo M, Yagi T, Fujisawa H: A requirement for neuropilin-1 in embryonic vessel formation. Development 1999, 126:4895-4902[Abstract]
  41. Migdal M, Huppertz B, Tessler S, Comforti A, Shibuya M, Reich R, Baumann H, Neufeld G: Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem 1998, 273:22272-22278[Abstract/Free Full Text]
  42. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M: Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998, 92:735-745[Medline]
  43. Dor Y, Keshet E: Ischemia-driven angiogenesis. Trends Cardiovasc Med 1997, 7:289-294
  44. Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992, 359:843-845[Medline]
  45. Shweiki D, Neeman M, Itin A, Keshet E: Induction of vascular endothelial growth factor expression by hypoxia and by glucose deficiency in multicell spheroids: implications for tumor angiogenesis. Proc Natl Acad Sci USA 1995, 92:768-772[Abstract/Free Full Text]
  46. Beerepoot LV, Shima DT, Kuroki M, Yeo KT, Voest EE: Up-regulation of vascular endothelial growth factor production by iron chelators. Cancer Res 1996, 56:3747-3751[Abstract/Free Full Text]
  47. Gleadle JM, Ebert BL, Firth JD, Ratcliffe PJ: Regulation of angiogenic growth factor expression by hypoxia, transition metals, and chelating agents. Am J Physiol 1995, 268:C1362-C1368[Abstract/Free Full Text]
  48. Levy AP, Levy NS, Goldberg MA: Hypoxia-inducible protein binding to vascular endothelial growth factor mRNA and its modulation by the von Hippel-Lindau protein. J Biol Chem 1996, 271:25492-25497[Abstract/Free Full Text]
  49. Gnarra JR, Ward JM, Porter FD, Wagner JR, Devor DE, Grinberg A, Emmert-Buck MR, Westphal H, Klausner RD, Linehan WM: Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc Natl Acad Sci USA 1997, 94:9102-9107[Abstract/Free Full Text]
  50. Semenza GL: Transcriptional regulation by hypoxia-inducible factor-1. Trends Cadiovasc Med 1996, 6:151-157
  51. Carmeliet P, Moons L, Dewerchin M, Mackman N, Luther T, Breier G, Ploplis V, Muller M, Nagy A, Plow E, Gerard R, Edgington T, Risau W, Collen D: Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system. Ann NY Acad Sci 1997, 811:191-206[Abstract/Free Full Text]
  52. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, Powell-Braxton L, Hillan KJ, Moore MW: Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996, 380:439-442[Medline]
  53. Stein I, Itin A, Einat P, Skaliter R, Grossman Z, Keshet E: Translation of vascular endothelial growth factor mRNA by internal ribosome entry: implications for translation under hypoxia. Mol Cell Biol 1998, 18:3112-3119[Abstract/Free Full Text]
  54. Perkett EA, Klekamp JG: Vascular endothelial growth factor expression is decreased in rat lung following exposure to 24 or 48 hours of hyperoxia: implications for endothelial cell survival. Chest 1998, 114:S52-S53[Medline]
  55. Pierce EA, Foley ED, Smith LE: Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity [published erratum appears in Arch Ophthalmol 1997, 115: 427]. Arch Ophthalmol 1996, 114:1219-1228[Abstract]
  56. Alon T, Hemo I, Itin A, Pe’er J, Stone J, Keshet E: Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1995, 1:1024-1028[Medline]
  57. Yamada H, Yamada E, Hackett SF, Ozaki H, Okamoto N, Campochiaro PA: Hyperoxia causes decreased expression of vascular endothelial growth factor and endothelial cell apoptosis in adult retina. J Cell Physiol 1999, 179:149-156[Medline]
  58. Brooks SE, Gu X, Kaufmann PM, Marcus DM, Caldwell RB: Modulation of VEGF production by pH and glucose in retinal Muller cells. Curr Eye Res 1998, 17:875-882[Medline]
  59. Natarajan R, Bai W, Lanting L, Gonzales N, Nadler J: Effects of high glucose on vascular endothelial growth factor expression in vascular smooth muscle cells. Am J Physiol 1997, 273:H2224-H2231
  60. Williams B, Gallacher B, Patel H, Orme C: Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes 1997, 46:1497-1503[Abstract]
  61. Park SH, Kim KW, Lee YS, Baek JH, Kim MS, Lee YM, Lee MS, Kim YJ: Hypoglycemia-induced VEGF expression is mediated by intracellular Ca2+ and protein kinase C signaling pathway in HepG2 human hepatoblastoma cells. Int J Mol Med 2001, 7:91-96[Medline]
  62. Eichler W, Kuhrt H, Hoffmann S, Wiedemann P, Reichenbach A: VEGF release by retinal glia depends on both oxygen and glucose supply. Neuroreport 2000, 11:3533-3537[Medline]
  63. Lu M, Amano S, Miyamoto K, Garland R, Keough K, Qin W, Adamis AP: Insulin-induced vascular endothelial growth factor expression in retina. Invest Ophthalmol Vis Sci 1999, 40:3281-3286[Abstract/Free Full Text]
  64. Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B: Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1 alpha/ARNT. EMBO J 1998, 17:5085-5094[Medline]
  65. Kim NH, Jung HH, Cha DR, Choi DS: Expression of vascular endothelial growth factor in response to high glucose in rat mesangial cells. J Endocrinol 2000, 165:617-624[Abstract]
  66. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus: The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993, 329:977–986
  67. Pettersson A, Nagy JA, Brown LF, Sundberg C, Morgan E, Jungles S, Carter R, Krieger JE, Manseau EJ, Harvey VS, Eckelhoefer IA, Feng D, Dvorak AM, Mulligan RC, Dvorak HF: Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab Invest 2000, 80:99-115[Medline]
  68. Duh E, Aiello LP: Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. Diabetes 1999, 48:1899-1906[Abstract]



This article has been cited by other articles:


Home page
 Toxicol PatholHome page
A. P. Hall
Review of the Pericyte during Angiogenesis and its Role in Cancer and Diabetic Retinopathy
Toxicol Pathol, October 1, 2006; 34(6): 763 - 775.
[Full Text] [PDF]

Home page
 Neuro OncolHome page
G. Bergers and S. Song
The role of pericytes in blood-vessel formation and maintenance
Neuro-oncol, October 1, 2005; 7(4): 452 - 464.
[Abstract] [PDF]

Home page
 J. Biol. Chem.Home page
K. Omori, K. Naruishi, F. Nishimura, H. Yamada-Naruishi, and S. Takashiba
High Glucose Enhances Interleukin-6-induced Vascular Endothelial Growth Factor 165 Expression via Activation of Gp130-mediated p44/42 MAPK-CCAAT/Enhancer Binding Protein Signaling in Gingival Fibroblasts
J. Biol. Chem., February 20, 2004; 279(8): 6643 - 6649.
[Abstract] [Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
M. Khamaisi, B. F. Schrijvers, A. S. De Vriese, I. Raz, and A. Flyvbjerg
The emerging role of VEGF in diabetic kidney disease
Nephrol. Dial. Transplant., August 1, 2003; 18(8): 1427 - 1430.
[Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
M. Khamaisi, B. F. Schrijvers, A. S. De Vriese, I. Raz, and A. Flyvbjerg
The emerging role of VEGF in diabetic kidney disease
Nephrol. Dial. Transplant., August 1, 2003; 18(88): 1427 - 1430.
[Full Text]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
K. Hirata, T.-S. Li, M. Nishida, H. Ito, M. Matsuzaki, S. Kasaoka, and K. Hamano
Autologous bone marrow cell implantation as therapeutic angiogenesis for ischemic hindlimb in diabetic rat model
Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H66 - H70.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
J. T. Rosenbaum
Sugar Creates a Sticky Business: Round Up the Usual Suspects
Am. J. Pathol., May 1, 2002; 160(5): 1547 - 1550.
[Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Benjamin, L. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Benjamin, L. E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS