Glucose, VEGF-A, and Diabetic Complications
2001; Elsevier BV; Volume: 158; Issue: 4 Linguagem: Inglês
10.1016/s0002-9440(10)64066-7
ISSN1525-2191
Autores Tópico(s)Retinal Imaging and Analysis
ResumoDiabetes 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 colleagues1Pinter 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: 1199-1206Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar 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.2Aiello 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: 1480-1487Crossref PubMed Scopus (3436) Google Scholar, 3Adamis 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: 445-450Abstract Full Text PDF PubMed Scopus (1211) Google Scholar, 4Boulton M Foreman D Williams G McLeod D VEGF localisation in diabetic retinopathy.Br J Ophthalmol. 1998; 82: 561-568Crossref PubMed Scopus (175) Google Scholar, 5Burgos 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: 1107-1109Crossref PubMed Scopus (101) Google Scholar, 6Katsura 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: 1759-1763Crossref PubMed Scopus (86) Google Scholar, 7Pe'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: 241-245Crossref PubMed Scopus (171) Google Scholar Additionally, in specimens of diabetic retinas increased expression of VEGF-A and its three receptors has been extensively demonstrated.8Lip 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: 2115-2119PubMed Google Scholar, 9Ishida 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: 1649-1656PubMed Google Scholar, 10Smith 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: 486-494Crossref PubMed Scopus (47) Google Scholar Other growth factors, such as IGF-1 and its receptor, have been shown to collaborate with VEGF-A to increase retinal neovascularization.11Smith 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: 1390-1395Crossref PubMed Scopus (501) Google Scholar 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.12Marsh 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: 1375-1380Crossref PubMed Scopus (46) Google Scholar And importantly, antagonists of VEGF and its receptors have been shown to reduce retinopathy in animal models.13Ozaki 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: 697-707Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar, 14Smith 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: 101-111PubMed Google Scholar, 15Aiello 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: 10457-10461Crossref PubMed Scopus (1172) Google Scholar, 16Robinson 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: 4851-4856Crossref PubMed Scopus (352) Google Scholar VEGF-A function to induce permeability is also a likely contributor to the vascular leakage that greatly contributes to the morbidity of diabetic retinopathy.17Aiello 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: 1473-1480Crossref PubMed Google Scholar, 18Murata 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: 48-52Crossref PubMed Scopus (204) Google Scholar 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.19Tsurumi 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: 3281-3290Crossref PubMed Scopus (374) Google Scholar, 20Isner 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: 959-988Crossref PubMed Scopus (145) Google Scholar, 21Baumgartner 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: 1114-1123Crossref PubMed Scopus (1079) Google Scholar, 22Baumgartner I Isner JM Stimulation of peripheral angiogenesis by vascular endothelial growth factor (VEGF).Vasa. 1998; 27: 201-206PubMed Google Scholar 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.23Rivard 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: 355-363Abstract Full Text Full Text PDF PubMed Scopus (412) Google Scholar Samii and colleagues24Samii 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: 159-162Crossref PubMed Scopus (99) Google Scholar 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.25Cooper 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: 2229-2239Crossref PubMed Scopus (420) Google Scholar 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.26Tilton 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: 2192-2202Crossref PubMed Scopus (176) Google Scholar, 27Stephan 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: 1771-1778Crossref PubMed Scopus (13) Google Scholar The study presented in this issue of The American Journal of Pathology by Pinter and colleagues1Pinter 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: 1199-1206Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar 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.28Ferencz C Rubin JD McCarter RJ Clark EB Maternal diabetes and cardiovascular malformations: predominance of double outlet right ventricle and truncus arteriosus.Teratology. 1990; 41: 319-326Crossref PubMed Scopus (126) Google Scholar 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.29Eriksson UJ Borg LA Forsberg H Styrud J Diabetic embryopathy. 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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.36Miquerol L Langille BL Nagy A Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression.Development. 2000; 127: 3941-3946Crossref PubMed Google Scholar 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-A165added 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.37DiSalvo 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: 7717-7723Crossref PubMed Scopus (245) Google Scholar, 38Park JE Chen HH Winer J Houck KA Ferrara N Placenta growth factor. 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92: 735-745Abstract Full Text Full Text PDF PubMed Scopus (2088) Google Scholar 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.43Dor Y Keshet E Ischemia-driven angiogenesis.Trends Cardiovasc Med. 1997; 7: 289-294Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 44Shweiki D Itin A Soffer D Keshet E Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.Nature. 1992; 359: 843-845Crossref PubMed Scopus (4177) Google Scholar, 45Shweiki 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: 768-772Crossref PubMed Scopus (540) Google Scholar, 46Beerepoot LV Shima DT Kuroki M Yeo KT Voest EE Up-regulation of vascular endothelial growth factor production by iron chelators.Cancer Res. 1996; 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18: 3112-3119Crossref PubMed Scopus (426) Google Scholar On the counter side, increased oxygen (hyperoxia)54Perkett 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-S53Crossref PubMed Google Scholar, 55Pierce 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: 1219-1228Crossref PubMed Scopus (437) Google Scholar, 56Alon 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: 1024-1028Crossref PubMed Scopus (1422) Google Scholar, 57Yamada 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: 149-156Crossref PubMed Scopus (81) Google Scholar and increased glucose (hyperglycemia)58Brooks 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: 875-882Crossref PubMed Scopus (62) Google Scholar, 59Natarajan 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-H2231PubMed Google Scholar 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,1Pinter 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: 1199-1206Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar 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.45Shweiki 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: 768-772Crossref PubMed Scopus (540) Google Scholar In vitro experiments supporting this glucose regulation have been performed on tumor cells, glial cells, retinal Muller cells, and vascular smooth muscle cells.58Brooks 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: 875-882Crossref PubMed Scopus (62) Google Scholar, 59Natarajan 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-H2231PubMed Google Scholar, 60Williams 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: 1497-1503Crossref PubMed Google Scholar, 61Park 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: 91-96PubMed Google Scholar, 62Eichler W Kuhrt H Hoffmann S Wiedemann P Reichenbach A VEGF release by retinal glia depends on both oxygen and glucose supply.Neuroreport. 2000; 11: 3533-3537Crossref PubMed Scopus (74) Google Scholar Moreover, similar to hypoglycemia, in vitro, acute insulin treatment induced VEGF-A expression.63Lu 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: 3281-3286PubMed Google Scholar Insulin has also been reported to regulate transcription via the hypoxia-inducible transcription factors.64Zelzer 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: 5085-5094Crossref PubMed Scopus (498) Google Scholar One report suggesting a contrary effect of glucose on VEGF-A is specific to mesangial cells of the kidney.65Kim 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: 617-624Crossref PubMed Scopus (72) Google Scholar 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.66The 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: 977-986Crossref PubMed Scopus (22937) Google Scholar 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.67Pettersson 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: 99-115Crossref PubMed Scopus (363) Google Scholar 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,68Duh E Aiello LP Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox.Diabetes. 1999; 48: 1899-1906Crossref PubMed Scopus (282) Google Scholar 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.
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