Increased Intraocular Insulin-like Growth Factor-I Triggers Blood-Retinal Barrier Breakdown

Blood-retinal barrier (BRB) breakdown is a key event in diabetic retinopathy and other ocular disorders that leads to increased retinal vascular permeability. This causes edema and tissue damage resulting in visual impairment. Insulin-like growth factor-I (IGF-I) is involved in these processes, although the relative contribution of increased systemic versus intraocular IGF-I remains controversial. Here, to elucidate the role of this factor in BRB breakdown, transgenic mice with either local or systemic elevations of IGF-I have been examined. High intraocular IGF-I, resulting from overexpression of IGF-I in the retina, increased IGF-I receptor content and signaling and led to accumulation of vascular endothelial growth factor. This was parallel to up-regulation of vascular Intercellular adhesion molecule I and retinal infiltration by bone marrow-derived microglial cells. These alterations resulted in increased vessel paracellular permeability to both low and high molecular weight compounds in IGF-I-overexpressing retinas and agreed with the loss of vascular tight junction integrity observed by electron microscopy and the altered junctional protein content. In contrast, mice with chronically elevated serum IGF-I did not show alterations in the retinal vasculature structure and permeability, indicating that circulating IGF-I cannot initiate BRB breakdown. Consistent with a key role of IGF-I signaling in retinal diseases, a strong up-regulation of the IGF-I receptor in human retinas with marked gliosis was also observed. Thus, this study demonstrates that intraocular IGF-I, but not systemic IGF-I, is sufficient to trigger processes leading to BRB breakdown and increased retinal vascular permeability. Therefore, therapeutic interventions designed to counteract local IGF-I effects may prove successful to prevent BRB disruption. Blood-retinal barrier (BRB) breakdown is a key event in diabetic retinopathy and other ocular disorders that leads to increased retinal vascular permeability. This causes edema and tissue damage resulting in visual impairment. Insulin-like growth factor-I (IGF-I) is involved in these processes, although the relative contribution of increased systemic versus intraocular IGF-I remains controversial. Here, to elucidate the role of this factor in BRB breakdown, transgenic mice with either local or systemic elevations of IGF-I have been examined. High intraocular IGF-I, resulting from overexpression of IGF-I in the retina, increased IGF-I receptor content and signaling and led to accumulation of vascular endothelial growth factor. This was parallel to up-regulation of vascular Intercellular adhesion molecule I and retinal infiltration by bone marrow-derived microglial cells. These alterations resulted in increased vessel paracellular permeability to both low and high molecular weight compounds in IGF-I-overexpressing retinas and agreed with the loss of vascular tight junction integrity observed by electron microscopy and the altered junctional protein content. In contrast, mice with chronically elevated serum IGF-I did not show alterations in the retinal vasculature structure and permeability, indicating that circulating IGF-I cannot initiate BRB breakdown. Consistent with a key role of IGF-I signaling in retinal diseases, a strong up-regulation of the IGF-I receptor in human retinas with marked gliosis was also observed. Thus, this study demonstrates that intraocular IGF-I, but not systemic IGF-I, is sufficient to trigger processes leading to BRB breakdown and increased retinal vascular permeability. Therefore, therapeutic interventions designed to counteract local IGF-I effects may prove successful to prevent BRB disruption. The BRB 5The abbreviations used are: BRBblood-retinal barrierIGFinsulin-like growth factorIGF-IRIGF-I receptorTJtight junctionBMbone marrowGFAPglial fibrillary acidic proteinConAconcanavalin AHRPhorseradish peroxidaseZOzonula occludensVEGFvascular endothelial (VE) growth factorICAM-1intercellular adhesion molecule 1GHgrowth hormonebGHbovine GHTgtransgenicGFPgreen fluorescent protein. is a selective diffusion barrier that isolates the retina from the blood, maintaining the appropriate milieu for optimal retinal function and excluding potentially harmful stimuli, therefore acting as a critical protective barrier. The BRB consists of outer and inner components. The outer BRB is formed by the retinal pigmentary epithelium, which separates photoreceptors from choroidal permeable vessels. The inner BRB is determined by the presence of tight junctions (TJs) between the endothelial cells of retinal vessels, which limits paracellular flux. In addition, retinal vessels are partially sheathed by glial end-foot processes. Although not considered direct components of the inner BRB, glial cells could play a key role in its formation, maintenance, and breakdown (1Gardner T.W. Antonetti D.A. Barber A.J. LaNoue K.F. Levison S.W. Surv. Ophthalmol. 2002; 47: S253-S262Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar). The disruption of the BRB is an important feature not only of non-proliferative and proliferative diabetic retinopathy but also of other diverse ocular disorders (2Adamis A. Br. J. Ophthalmol. 2002; 86: 363-365Crossref PubMed Scopus (324) Google Scholar, 3Kent D. Vinores S. Campochiaro P. Br. J. Ophthalmol. 2000; 84: 542-545Crossref PubMed Scopus (73) Google Scholar). Increased vascular permeability results in extravasation of plasma components leading to edema. If the accumulation of fluids threatens the macula it poses a serious risk to visual function. Indeed, macular edema is a leading cause of visual loss among diabetic patients (3Kent D. Vinores S. Campochiaro P. Br. J. Ophthalmol. 2000; 84: 542-545Crossref PubMed Scopus (73) Google Scholar). blood-retinal barrier insulin-like growth factor IGF-I receptor tight junction bone marrow glial fibrillary acidic protein concanavalin A horseradish peroxidase zonula occludens vascular endothelial (VE) growth factor intercellular adhesion molecule 1 growth hormone bovine GH transgenic green fluorescent protein. IGF-I has been associated with the pathogenesis of BRB breakdown. Although most studies report an increase of intraocular IGF-I levels in diabetic patients (4Merimee T.J. Zapf J. Froesch E.R. N. Engl. J. Med. 1983; 309: 527-530Crossref PubMed Scopus (278) Google Scholar, 5Grant M. Russell B. Fitzgerald C. Merimee T.J. Diabetes. 1986; 35: 416-420Crossref PubMed Google Scholar), the source of IGF-I is not clear (6Shaw L.C. Grant M.B. Rev. Endocr. Metab. Disord. 2004; 5: 199-207Crossref PubMed Scopus (25) Google Scholar, 7Frystyk J. Horm. Metab. Res. 2005; 37: 44-48Crossref PubMed Scopus (33) Google Scholar), and the relative contribution of local versus serum IGF-I in initiating ocular pathology is unknown. IGF-I is a potent inducer of vascular endothelial growth factor (VEGF) (8Punglia R.S. Lu M. Hsu J. Kuroki M. Tolentino M.J. Keough K. Levy A.P. Levy N.S. Goldberg M.A. D'Amato R.J. Adamis A.P. Diabetes. 1997; 46: 1619-1626Crossref PubMed Google Scholar), a pro-angiogenic factor that increases vessel permeability (1Gardner T.W. Antonetti D.A. Barber A.J. LaNoue K.F. Levison S.W. Surv. Ophthalmol. 2002; 47: S253-S262Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar). We and others have shown in animal models that IGF-I participates in the pathophysiology of diabetic retinopathy by inducing retinal VEGF expression (9Ruberte J. Ayuso E. Navarro M. Carretero A. Nacher V. Haurigot V. George M. Llombart C. Casellas A. Costa C. Bosch A. Bosch F. J. Clin. Invest. 2004; 113: 1149-1157Crossref PubMed Scopus (159) Google Scholar, 10Poulaki V. Joussen A.M. Mitsiades N. Mitsiades C.S. Iliaki E.F. Adamis A.P. Am. J. Pathol. 2004; 165: 457-469Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). In diabetic retinopathy there is a correlation between VEGF vitreous levels and macular edema (11Funatsu H. Yamashita H. Nakamura S. Mimura T. Eguchi S. Noma H. Hori S. Ophthalmology. 2006; 113: 294-301Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar). Aqueous humor levels of VEGF are also higher in diabetic patients with macular edema, and levels correlate with disease severity (12Funatsu H. Yamashita H. Noma H. Mimura T. Yamashita T. Hori S. Am. J. Ophthalmol. 2002; 133: 70-77Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 13Patel J.I. Tombran-Tink J. Hykin P.G. Gregor Z.J. Cree I.A. Exp. Eye Res. 2006; 82: 798-806Crossref PubMed Scopus (116) Google Scholar). Moreover, the early BRB breakdown observed in experimental diabetes coincides with an increase in VEGF (14Qaum T. Xu Q. Joussen A.M. Clemens M.W. Qin W. Miyamoto K. Hassessian H. Wiegand S.J. Rudge J. Yancopoulos G.D. Adamis A.P. Invest. Ophthalmol. Vis. Sci. 2001; 42: 2408-2413PubMed Google Scholar). To discern the contribution of intraocular versus circulating IGF-I in triggering VEGF production and BRB disruption, in this study we have examined the retinas of two transgenic animal models with elevated IGF-I levels either locally or in the serum. We have found that only IGF-I generated within the eye may trigger the breakdown of the BRB in mice, whereas increased circulating IGF-I did not alter retinal vascular permeability. Therefore, therapeutic interventions designed to counteract local IGF-I effects may prove successful to prevent BRB disruption. CD1 or C57Bl6/SJL heterozygous mice overexpressing IGF-I in the retina (9Ruberte J. Ayuso E. Navarro M. Carretero A. Nacher V. Haurigot V. George M. Llombart C. Casellas A. Costa C. Bosch A. Bosch F. J. Clin. Invest. 2004; 113: 1149-1157Crossref PubMed Scopus (159) Google Scholar) were used for permeability studies or as recipients of bone marrow (BM) transplantation, respectively. Paracellular transport was studied in 4-month-old CD1 TgIGF-I females. To investigate the long term effects of increased serum IGF-I, C57Bl6/SJL transgenic mice expressing bovine GH in the liver were used (15McGrane M. De Vente J. Yun J. Bloom J. Park E. Wynshaw-Boris A. Wagner T. Rottman F. Hanson R. J. Biol. Chem. 1988; 263: 11443-11451Abstract Full Text PDF PubMed Google Scholar). Animal care and experimental procedures were approved by the Ethics Committee in Animal and Human Experimentation of Universitat Autònoma de Barcelona. Human retinas were obtained from corpses donated to Universitat Autònoma de Barcelona Medical School. Donors 1, 3, and 5 were 83-, 99-, and 85-year-old males. Donors 2 and 4 were females of 86 and 89 years of age. Donor 5 died from diabetic cardiomyopathy. Retinas or whole eyes were homogenized in lysis buffer, separated by 12% SDS-PAGE, and analyzed by immunoblotting with anti-IGF-I receptor (ab39675, Abcam), anti-Akt (#9272, Cell Signaling), anti-Akt-P (#9271, Cell Signaling), anti-VEGF (ab9953, Abcam), anti-glial fibrillary acidic protein (GFAP) (Z0334, DAKO), anti-intercellular adhesion molecule 1 (ICAM-1; AF796, R&D Systems), anti-occludin (711500, Zymed Laboratories Inc., Invitrogen), anti-claudin-1 (717800, Zymed Laboratories Inc.), anti-claudin-5 (341600, Zymed Laboratories Inc.), anti-VE-cadherin (AF1002, R&D Systems), or anti-tubulin (ab4074, Abcam). Detection was performed using ECL Plus detection reagent (Amersham Biosciences). Pixel intensity of the bands obtained was determined with GeneSnap software for Gene Genius Bio Imaging eye were with anti-IGF-I and retinas were with Zymed Laboratories Inc.), or fluorescent protein Abcam). were obtained with a was as Vinores K. T. T. S. Campochiaro Invest. Ophthalmol. Vis. Sci. 2002; Google Scholar). of retina to were In BRB was performed of (Amersham Biosciences). were with the molecular that Vinores K. T. T. S. Campochiaro Invest. Ophthalmol. Vis. Sci. 2002; Google Scholar) were extravasation was analyzed of horseradish peroxidase were using a To paracellular permeability, a for A.J. Antonetti D.A. Invest. Ophthalmol. Vis. Sci. PubMed Scopus Google Scholar) with concanavalin A was to to vascular the and the A.J. Antonetti D.A. Invest. Ophthalmol. Vis. Sci. PubMed Scopus Google Scholar, J. 1986; PubMed Scopus Google Scholar), of increased paracellular permeability. integrity was studied by electron microscopy in obtained of were was the vessel marrow cells from C57Bl6/SJL mice expressing M. M. K. T. 1997; PubMed Scopus Google Scholar) were to was determined by mice cells of and this was 4 of the retinas and was performed using by cells. In was performed with a were with and was and the eye was studied of of green for of the and retinal vasculature retinal a of are as the between were by were considered In this study and transgenic mice overexpressing IGF-I in the retina (9Ruberte J. Ayuso E. Navarro M. Carretero A. Nacher V. Haurigot V. George M. Llombart C. Casellas A. Costa C. Bosch A. Bosch F. J. Clin. Invest. 2004; 113: 1149-1157Crossref PubMed Scopus (159) Google Scholar) were IGF-I in the humor of whereas it was in humor of mice This accumulation of intraocular IGF-I resulted from local expression both and TgIGF-I have serum IGF-I IGF-I its and of which is in the retina Invest. Ophthalmol. Vis. Sci. 37: Google Scholar). of an increase in in transgenic retinas The of was in and transgenic with strong in cells of the in processes, and in photoreceptors cells and endothelial cells also In TgIGF-I in processes was observed. The increased levels of IGF-I and its receptor were associated with a marked increase in protein a of V. Joussen A.M. Mitsiades N. Mitsiades C.S. Iliaki E.F. Adamis A.P. Am. J. Pathol. 2004; 165: 457-469Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar) The of the IGF-I led to VEGF accumulation in the humor of TgIGF-I To study the of locally increased IGF-I the permeability of retinal vessels, were of BRB breakdown in mice Vinores K. T. T. S. Campochiaro Invest. Ophthalmol. Vis. Sci. 2002; Google Scholar). TgIGF-I a increase in from retinal vessels and of A was observed in although the was not Thus, the breakdown of the BRB to of low molecular weight is from an early in In of a to BRB we a in the of a low molecular weight and the of an molecular that were used as a BRB disruption Vinores K. T. T. S. Campochiaro Invest. Ophthalmol. Vis. Sci. 2002; Google Scholar). was in the eye that but not in the eye that This was of from retinal vessels intraocular was in either of the eyes of In contrast, fluorescent of intensity were observed in both eyes of These were with the results obtained with permeability to was analyzed in retinal of from mice of its detection within the vessel In was the of cells the vessel in and also cells in the retinal that the cells that from the retinal permeability studies that increased intraocular IGF-I is sufficient to trigger BRB breakdown. 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Pathol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). increase in levels was observed in transgenic retinas Moreover, in retinal transgenic vessels These results an in To cells were to transgenic cells from mice M. M. K. T. 1997; PubMed Scopus Google Scholar) were mice from mice that retinal cells and with microglial In both and transgenic microglial cells were in the retinal A increase in microglial cells was found in transgenic retinas versus These that local increases in IGF-I, acting or cells which cells with results that increased intraocular IGF-I BRB breakdown. To high circulating IGF-I could also BRB transgenic mice overexpressing bovine growth hormone in the liver of the (15McGrane M. De Vente J. Yun J. Bloom J. Park E. Wynshaw-Boris A. Wagner T. Rottman F. Hanson R. J. Biol. Chem. 1988; 263: 11443-11451Abstract Full Text PDF PubMed Google Scholar, A. Yun Hanson Bosch F. J. PubMed Scopus Google Scholar) were examined. of these mice high serum IGF-I levels Moreover, transgenic mice were but and A. Yun Hanson Bosch F. J. PubMed Scopus Google Scholar). chronically elevated levels of circulating IGF-I in IGF-I was in humor from indicating that IGF-I from the did not within the alterations were observed in the eyes of eye of the or retina and the retina and In addition, retinal vessels of and the and the and of was to that of mice vessel permeability was with both the and the in BRB was in and Consistent with and VEGF were observed in indicating the of that VEGF and levels were in and these results that chronically elevated serum IGF-I is to alter retinal vascular permeability and initiate In mice, increases in local IGF-I led to BRB breakdown, which resulted from up-regulation of and IGF-I expression was analyzed in retinas from human a marked up-regulation of was observed in with clear of overexpression was in cells of These that increased IGF-I signaling may also involved in processes leading to retinal vascular pathology in The study that locally increased IGF-I is to trigger BRB breakdown, a role of IGF-I in BRB In mice with intraocular accumulation of IGF-I, was increased in leading to increased IGF-I signaling and accumulation of levels increase as (9Ruberte J. Ayuso E. Navarro M. Carretero A. Nacher V. Haurigot V. George M. Llombart C. Casellas A. Costa C. Bosch A. Bosch F. J. Clin. Invest. 2004; 113: 1149-1157Crossref PubMed Scopus (159) Google Scholar). The up-regulation of in cells has also been observed in retinopathy M. M. D. P. Invest. Ophthalmol. Vis. Sci. PubMed Scopus Google Scholar). a of these TgIGF-I increased retinal permeability to low and high molecular weight compounds in and In diabetic BRB breakdown has also been to retinal and (14Qaum T. Xu Q. Joussen A.M. Clemens M.W. Qin W. Miyamoto K. Hassessian H. Wiegand S.J. Rudge J. Yancopoulos G.D. Adamis A.P. Invest. Ophthalmol. Vis. Sci. 2001; 42: 2408-2413PubMed Google Scholar). In with paracellular transport to has been observed in diabetic or of VEGF A.J. Antonetti D.A. Invest. Ophthalmol. Vis. Sci. PubMed Scopus Google Scholar). The disruption of that the paracellular was by electron microscopy in which was within and in cells of the vessel of in may increased paracellular permeability. We observed the endothelial in TgIGF-I vessels, which with that increased paracellular is associated with of from the S. M. D. W. Res. 2002; PubMed Scopus Google Scholar). the other in content were found in has been to in associated with increased BRB permeability A.J. Antonetti D.A. Invest. Ophthalmol. Vis. Sci. PubMed Scopus Google Scholar, D.A. Barber A.J. S. E. T.W. Diabetes. 47: PubMed Scopus Google Scholar). the that mice for the disruption of the have of and M. M. H. M. H. T. S. Biol. 2000; PubMed Scopus Google Scholar) that is not for has been that and not the of TgIGF-I retinas which has also been in experimental a with altered BRB H. R. J. Invest. Ophthalmol. Vis. Sci. 2005; 46: PubMed Scopus (73) Google Scholar). In contrast, the content of was not in study or of experimental diabetes or of VEGF A.J. Antonetti D.A. Invest. Ophthalmol. Vis. Sci. PubMed Scopus Google Scholar). Although a report has to BRB breakdown in diabetes D. P.G. A. Diabetes. PubMed Scopus Google Scholar), in were in This with the that are the key molecular permeability in a barrier E. Rev. Cell Biol. 2004; 5: PubMed Scopus Google Scholar). levels of intraocular IGF-I, transgenic retinas a increase in vascular permeability, that IGF-I BRB breakdown but that other to its TgIGF-I retinas marked gliosis (9Ruberte J. Ayuso E. Navarro M. Carretero A. Nacher V. Haurigot V. George M. Llombart C. Casellas A. Costa C. Bosch A. Bosch F. J. Clin. Invest. 2004; 113: 1149-1157Crossref PubMed Scopus (159) Google Scholar). is a feature of retinal pathology (1Gardner T.W. Antonetti D.A. Barber A.J. LaNoue K.F. Levison S.W. Surv. Ophthalmol. 2002; 47: S253-S262Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar, M. M. Diabetes. 47: PubMed Scopus Google Scholar). cells may BRB (1Gardner T.W. Antonetti D.A. Barber A.J. LaNoue K.F. Levison S.W. Surv. Ophthalmol. 2002; 47: S253-S262Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar). glial cells VEGF in human diabetic retinopathy A. D. Invest. Ophthalmol. Vis. Sci. 1997; Google Scholar) and in transgenic (9Ruberte J. Ayuso E. Navarro M. Carretero A. Nacher V. Haurigot V. George M. Llombart C. Casellas A. Costa C. Bosch A. Bosch F. J. Clin. Invest. 2004; 113: 1149-1157Crossref PubMed Scopus (159) Google Scholar). of the as a of increased local IGF-I could damage to the retinal retinal has been associated with the pathogenesis of BRB breakdown (2Adamis A. Br. J. Ophthalmol. 2002; 86: 363-365Crossref PubMed Scopus (324) Google Scholar). key of the of circulating and is retinal the of a of among which is VEGF (2Adamis A. Br. J. Ophthalmol. 2002; 86: 363-365Crossref PubMed Scopus (324) Google Scholar, A.M. V. Qin W. B. Mitsiades N. Wiegand S.J. Rudge J. Yancopoulos G.D. Adamis A.P. Am. J. 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Therefore, high local IGF-I acting or VEGF increased the of to transgenic and this may have to the vascular The study that local IGF-I trigger BRB breakdown. the source of ocular IGF-I in diabetes is controversial. high circulating IGF-I, the retinas of were and IGF-I was in in with indicating that ocular IGF-I is not GH C. F. M. Diabetes. 2001; PubMed Scopus Google Scholar) and that levels of GH or IGF-I not correlate with circulating levels S. M. M.J. Horm. Metab. Res. PubMed Scopus Google Scholar). the retinal vasculature of alterations high circulating IGF-I from (15McGrane M. De Vente J. Yun J. Bloom J. Park E. Wynshaw-Boris A. Wagner T. Rottman F. Hanson R. J. Biol. Chem. 1988; 263: 11443-11451Abstract Full Text PDF PubMed Google Scholar), the of the retinal vasculature in The local effects of chronically elevated intraocular IGF-I observed in TgIGF-I (9Ruberte J. Ayuso E. Navarro M. Carretero A. Nacher V. Haurigot V. George M. Llombart C. Casellas A. Costa C. Bosch A. Bosch F. 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Metab. 2000; PubMed Scopus Google Scholar). these results the of of high circulating IGF-I the BRB and retinal Therefore, results from the two transgenic models that the source of increased intraocular IGF-I is to the circulating IGF-I, as in it could that increases in local IGF-I or increases of its receptor and signaling in the presence of IGF-I levels could trigger a retinal VEGF and other that initiate BRB breakdown and increase retinal vessel permeability. circulating IGF-I and other circulating may the barrier and the leading to a disruption of BRB and of the the that may to increased IGF-I expression in the retina remains although and retinal may play a We have also observed a strong increase of in human retinas with marked This that increased retinal IGF-I signaling may play a key role in the pathogenesis of retinopathy in an increase in retinal expression has been in with diabetes C. F. M. Diabetes. 2001; PubMed Scopus Google Scholar), and expression is in retinal endothelial cells from diabetic Grant M.B. Horm. Res. PubMed Scopus Google Scholar). Thus, in human diabetic increases of intraocular IGF-I may in increased IGF-I signaling overexpression of and this could play a key role in the and of the In this study that increased but not increased IGF-I trigger BRB breakdown. In mice with increased intraocular IGF-I, IGF-I acting or in with VEGF and led to BRB breakdown. the key role of local IGF-I in the of retinal vascular Moreover, results that or interventions designed to counteract the effects of local IGF-I could prove successful in the and of diabetic retinopathy and other ocular We C. and M. for R. W. Hanson for mice, and C. H. M. and V. for