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Growth Hormone & IGF Research
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Review
An ocular view of the IGF–IGFBP system
Dung V. Nguyen, Sergio Li Calzi, Lynn C. Shaw, Jennifer L. Kielczewski, Hannah E. Korah, Maria B. Grant ⁎Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, USA
IGFs and their binding proteins have been shown to exhibit both protective and deleterious effects in oculardisease. Recent studies have characterized the expression patterns of different IGFBPs in retinal layers andwithin the vitreous. IGFBP-3 has roles in vascular protection stimulating proliferation, migration, and differ-entiation of vascular progenitor cells to sites of injury. IGFBP-3 increases pericyte ensheathment and showsanti-inflammatory effects by reducing microglia activation in diabetes. IGFBP-5 has recently been linked tomediating fibrosis in proliferative vitreoretinopathy but also reduces neovascularization. Thus, the regulatorybalance between IGF and IGFBPs can have profound impact on target tissues. This review discusses recentfindings of IGF and IGFBP expression in the eye with relevance to different retinopathies.
Insulin-like growth factors (IGFs) are peptides produced in theliver and throughout most tissues that stimulate mitogenic activitythrough their interaction with IGF receptors (IGFRs) [1]. Two formshave been identified: IGF-I and IGF-II; they are regulated by insulin-like growth factor binding proteins (IGFBPs) and IGFBP proteases tocollectively form the IGF system. IGFBPs interact with a glycoprotein,the acid-labile subunit (ALS), and binds free IGF in serum to form aternary complex and modulate IGF binding to IGFRs on endothelium[2]. Of the IGFBPs, IGFBP-3 is most abundant in postnatal serum andcarries more than 75% of serum IGF-I and IGF-II in complexes [1,3].Other IGFBPs bind a small proportion of IGF and less than 1% of IGFsare circulating freely [2]. The existence of IGFBPs was postulated in the1960s but the definitive studies were carried in themid 1980s until suc-cessful cloning and sequencing of six IGFBPs (IGFBP-1 to IGFBP-6) in theearly 1990s [2,4–9]. Since then, nine IGFBP related proteins (IGFBP-rPs)sharing some homology have been identified. All bind to IGF althoughwith lower affinity than IGFBPs [10–12].
Serum IGF-I is synthesized and released from the liver followingactivation of hepatic receptors via binding of growth hormone (GH),so IGF-I may be important for regulating growth [13,14]. A dual effectortheory has been proposed suggesting that GH causes cell differentiationwhile IGF-I promotes cell proliferation [15]. Early studies in GHdeficientchildren showed that IGF-I has a major role in regulating fetal growth,
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especially during the third trimester [16]. Recent pharmacokinetic studieshave determined dosing parameters of IGF-I/IGFBP-3 to maintain IGF-Ilevels at normal physiologic range in preterm infants without significantchanges to blood pressure, heart rate, or blood glucose levels [17]. Pre-mature infants with insufficient IGF-I can be given exogenous IGF-I topromote normal vessel development and to prevent retinopathy of pre-maturity (ROP) [17,18].
Modulating IGFBP expression may have inhibitory or stimulatoryeffects depending on the microenvironment and cellular context[19–21]. IGF-I and IGF-II have been linked to atherosclerosis to stim-ulate vascular smooth muscle cell proliferation (VSMC) and maintainplaque stability [22,23]. Although VSMC proliferation may contributeto the development of plaques, it has also been suggested that reduc-ing IGF-I levels below physiologic levels may lead to loss of VSMC,destabilize plaques, and thus increase in risk of thrombosis [24]. Areduction in circulating IGF-I levels has been shown to promote ath-erosclerosis in Apolipoprotein E-deficient mice [25]. Increased IGFBP-1levels reduced plaque burden, lowers blood pressure, and confers pro-tection fromatherosclerosis inmice overexpressing IGFBP-1 [26]. Uponplaque inflammation, IGFBP-1 is activated to control SMC proliferationwhichmay regulatefibroproliferative processes and subsequently plaquestability [27].
In prostate cancer, IGFBP-3 has been shown to mediate anti-growth signals, induce apoptosis in prostate cancer cells, and displayantiangiogenic properties [28–32]. In breast cancer cells, IGFBP-3 ap-pears to maintain cell survival under adverse microenvironments bybinding to glucose-regulated protein 78 and stimulating autophagy[33]. IGFBP-3 can also bind to a cell death receptor, IGFBP-3R, that isexpressed in M12 human prostate cancer cells and MDA231 breastcancer cells [34]. IGFBP-3/IGFBP-3R mRNA expression is reduced in
46 D.V. Nguyen et al. / Growth Hormone & IGF Research 23 (2013) 45–52
invasive tissues compared to benign tissues [34]. Restoring the ex-pression of IGFBP-3/IGFBP-3R enhanced tumor suppressive activityby activating Caspase-8 signaling [34].
Most tissues can synthesize IGF-I, therefore locally derived IGF-Imayhave more dominant roles in regulating the tissue microenvironmentthan serum IGF-I [15,35]. Within the eye, IGF-I receptors (IGF-IR) arepresent on retinal microvascular cells and their activation increasesboth DNA synthesis and promotes migration [15,36,37]. Vitreal IGF-Ilevels were found to be increased in diabetic patients [14,15,38]. Thus,IGF-I may be involved in retinal neovascularization, which is a primarydeterminant for retinopathy of prematurity (ROP) or proliferativediabetic retinopathy (PDR) [15]. Numerous studies have identifiedexpression patterns of IGFBPs in the retina and vitreous humor whenexposed to certain microenvironments. The focus of this reviewwill examine recent findings of the IGF-IGFBP system and its role inretinopathy.
2. IGF/IGFBP expression in the eye
IGF-I and IGF-IR have been detected in retinal endothelial cells,lens epithelial cells, retinal pigment epithelium, cone photoreceptorcells, and Müller cells [39–43]. Using models of oxygen-induced reti-nopathy (OIR), microarrays determined differential global expressionprofiles between hypoxic and hyperoxic retinas. Retinas removedfrom hyperoxic chambers showed upregulation of genes associatedwith vasculogenesis, neurogenesis, and inflammation and includedIGFBP-3 [44]. Alternatively, IGFBP-7, or IGFBP-rP1, was downregulatedwhen compared to normoxic retinas [44].
Closer examination using laser capture microdissection identifiedlocalization and abundance of IGFs and IGFBPs [45]. IGF-IR expressionwas predominantly found in photoreceptor cells, which may be impor-tant for retinal vascular development since IGF-IR null mice showeddecreased retinal vasculature [45,46]. IGFBP-2, IGFBP-4, and IGFBP-5are expressed similarly between normoxic and hypoxic conditions.IGFBP-3 basal expression was lower, but was significantly induced tosimilar levels of other IGFBPs under hypoxia [45]. Therewere increasedmRNA levels of IGFBP-3 and IGFBP-5within neovascular tufts, howeverno functional protein levels were measured [45].
IGFBP levels in vitreous of the eye have been reported. Westernblot analyses using biotinylated IGF-II revealed that IGFBP-2 andIGFBP-3 were predominant in the vitreous, but a small ~29 kDa bandconfirmed by in vitro studies with IGFBP-3 protease indicated thatIGFBP-3 existed in a cleaved form [47]. Schoen et al. found the cleavedform of IGFBP-3 to be more prominent in diabetic vitreous humor,suggesting a role of IGFBP-3protease in regulating IGFBP-3 in the vitreous[48]. The functionality of the fragmented IGFBP-3 and significance ofIGFBP-3 proteases in the vitreous has not been determined.
(mRen-2)27, a hypertensive rat model with elevated serum andocular renin levels, was treated with streptozotocin to induce diabetesto evaluate expression of the IGF system [49]. In the diabetic state, over-all abundance of IGFBP-5 was increased in the cornea and iris whileIGFBP-6 was reduced [49]. IGFBP-1 was present in retinal layers withno change with diabetes whereas IGFBP-2, IGFBP-3, and IGFBP-4 werenot detected by in situ hybridization [49]. Differences in consensus ofmRNA expression of IGF system may be due to assay conditions andthe particular animal model [49,50].
The presence of IGFBPs both in the retina and in the vitreous tovarying levels depending on the model suggest that they may havefunctional roles in regulating ocular physiology. Current evidenceshows that IGFBPs play a key role in limiting free IGFs in circulationwhich can inhibit retinal angiogenesis growth and development. SinceIGFBP-3 is the major protein that binds to free IGF, the predominantlycleaved form in the vitreous of diabetic eyes may lead to altered regula-tion of IGFs [47,48,51–53]. Further studies are necessary to understandthe regulation of IGF axis expression and function as a protective orpathophysiological process.
3. Role of IGFBP-3 under hypoxia
Retinopathy is associated with both dysfunctional repair andmaintenance of the retinal vasculature. In diabetes associated retinalcomplications, endothelial progenitor cells (EPCs) displaying the CD34+
surface marker have reducedmigratory, proliferative, and differentiationpotential. CD34+ cells exposed with exogenous IGFBP-3 were able tomigrate in a dose-dependent manner and increase endothelial nitricoxide synthase (eNOS) activity, a prominent factor in vasodilation,suggesting that IGFBP-3 can stimulate recruitment of precursor cells[3,54]. In vivo studies support this finding through increased bonemarrow derived GFP+ cells in the retina in response to endothelialcell overexpression of IGFBP-3 (Fig. 1).
Migration of CD34+ progenitors represents a critical process forroutine vascular maintenance as well as repair of injuries. We havepreviously shown that IGFBP-3 promotes retinal repair by stimulatingbone marrow-derived cell homing following injury; many of thesemigrating cells are vascular progenitors [53]. Vasodilator-stimulatedphosphoprotein (VASP) plays a pivotal role in cell migration and itsactivation is nitric oxide (NO)-dependent [55,56]. IGFBP-3 also in-duces eNOS activation and subsequent NO generation. We, therefore,investigated whether IGFBP-3 treatment affected VASP redistributionin human microvascular endothelial cells. Treatment with IGFBP-3caused a rapid redistribution of VASP to the tip of lamellipodia pro-moting cell motility (Fig. 2). IGFBP-3-mediated VASP redistributionwas blocked by preincubation with by an NO scavenger [54].
CD34+ numbers were also lower in the retina in IGFBP-3 knockoutmice [57]. In vivo studies showed that overexpression of IGFBP-3,using a proliferating endothelial cell specific promoter, protectedagainst vaso-obliteration in an OIR model and also reduced preretinalneovascularization in a model of branch vein occlusion (BVO) [3,58].The laboratory of Lois Smith found similar results where low IGFBP-3was correlated with vaso-obliteration [57]. The study implicates arole of IGFBP-3 in recruiting vascular progenitor cells to sites of injuryfollowing hypoxia and administration of IGFBP-3 may be a treatmentstrategy for revascularization and repair.
IGFBP-3 has additional roles aside from recruiting hematopoieticstem cells (HSCs) and progenitor cells to sites of retinal injury. WhileIGFBP-3 can promote HSC differentiation to endothelial cells, it can alsoregulate differentiation into pericytes and astrocytes to stabilize the vas-culature [58]. Additionally, upon induction of retinal injury using laserphotocoagulation injury, injection of an endothelial specific IGFBP-3expressing plasmid showed increased pericyte ensheathment based onan observed increased in NG2+ immunoreactivity [58]. There was alsoa reduction in pericyte apoptosis based on less NG2+/TUNEL+ labelingcompared to contralateral uninjected and control-vector injected eyes[58].
In hypoxic environments, inflammatory responses are recapitulatedin the OIR model through the activation of resident microglia [58,59].IGFBP-3 attenuates inflammatory responses by increasing microgliaapoptosis and reducing the numbers of activated microglia [58]. Theanti-inflammatory roles of IGFBP-3 have been observed in tissuesother than the retina. IGFBP-3 has been shown to activate caspase ac-tivity in lungs of an asthmamousemodel to degrade inhibitor of kappaB alpha and nuclear factor kappa B [60]. Similarly, administration ofboth IGF-I and IGFBP-3 in children with burn injuries reduced inter-leukin (IL)-6, IL-1β and tumor necrosis factor-alpha inflammatorymarkers [61,62].
Hypoxia and ischemic injury can be attenuated with vasodilatoryresponses. We showed that IGFBP-3 can affect vasodilation in ratposterior cerebral arteries. IGFBP-3 administration displayed a dose-dependent decrease in artery constriction placed under intraluminalpressure [54]. The vasodilatory effect was lost in the presence of inhib-itors to eNOS [54,63]. IGFBP-3 stimulated NO release in intact arteriesthat is independent of calcium mediated NO release [54]. IGFBP-3by promoting NO generation and vasodilation may be important for
Fig. 1. Retinal vasculature in a GFP+ chimeric mouse (WT mouse undergoing bone marrow transplantation) that received within the vitreous liposomes containing a plasmidexpressing IGFBP-3 under an endothelial speciffic promoter. The mouse then was subjected to the retinal branch vein occlusion model. Three weeks after liposome injection,the mouse was sacrificed and a retinal flat mount was prepared. (A) The retinal vessels were labeled with rhodamine agglutinin (red) and imaged using confocal fluorescencemicroscopy. (B) Enhanced incorporation of GFP+ progenitor cells (green) into the retinal vessels is shown. (C) Merged channel. IGFBP-3's protective and reparative effects onthe vasculature may be, in part, the result of its ability to recruit endothelial progenitor cells, to sites of retinal injury.
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ROP and for counteracting the progression of non-proliferative diabeticretinopathy (NPDR) to proliferative diabetic retinopathy (PDR). Furtherstudies to determine reperfusion capability by IGFBP-3 throughNOpro-duction in the retina should be examined.
4. IGFBP-3 and blood retinal barrier integrity
Blood retinal barrier (BRB) breakdown is strongly associated withthedevelopment of ocular disease [64–66]. Emerging evidence indicatesthat IGFBP-3 may have roles that maintain and restore the integrity ofthe BRB following injury. We isolated a mutant IGFBP-3 that does notbind to IGF-I (IGFBP-3NB) and found it improved vascular barrier pro-tection andmaintained claudin-5 and vascular endothelial-cadherin ex-pression upon exposure to vascular endothelial growth factor (VEGF)[63,65]. Under normal physiological conditions, IGFBP-3 can counteractthe activation of VEGF by binding IGF-I, however these results show anIGF-I independent role of IGFBP-3 in protecting the BRB [63,65]. Addi-tionally, IGFBP-3 may protect the BRB by modulating inflammation.IGFBP-3NB was shown to reduce proinflammatory sphingomyelinaselevels in the retina [65].
5. Vascular protective signaling mechanism of IGFBP-3
The induction of recruitment of CD34+ cells to sites of vascularinjury involves a cascade of signaling mechanisms. IGFBP-3 binds toscavenger receptor class B, type1 (SR-B1), a receptor for high-density
lipoprotein (HDL) [67,68]. NO is generated upon activation of SR-B1by IGFBP-3 and subsequently by stimulation of eNOS activity [63,69].A later study found IGFBP-3 activates PI3K/Akt pathway throughSR-B1 [69]. IGFBP-3 also can stimulate sphingosine kinase (SphK)-1 ac-tivity which phosphorylates sphingosine to generate sphingosine-1-phosphate (S1P), a proangiogenic factor [63,69]. Mechanisms aresummarized in Fig. 3.
6. IGF axis in diabetes-induced retinopathy
Chronic hyperglycemia can influence cellular responses in thepresence of IGF-I. Bovine retinal endothelial cells (RECs) exposed tolow and high levels of glucose showed enhanced proliferation in thepresence of IGF-I [66,70]. Integrins may have roles in PDR progression[71]. IGF-I can activate αVβ3 integrin activation and maintain the sig-naling pathways that stimulate cell proliferation [66]. IGF-I protectedhumanRECs (HRECs) fromapoptosiswhen exposed to high glucose andserum starvation [72]. Exogenous IGFBP-3 induced a dose-dependentinhibition of HREC proliferation and at very high doses (1 mg/ml)increased apoptosis [72]. Alternatively, high glucose has also beenshown to increase expression of IGFBP-3 in proximal tubular epithelialcells and induce apoptosis [73]. In prostate cancer, tumor cell prolifer-ation was increased by over 3-fold in IGFBP-3 knockout lines [31].
VEGF-A is a major growth factor involved in ocular angiogenesis inretinopathy and its levels are correlated with neovascularization [74].IGFBP-4 and IGFBP-5have been found to counteract neovascularization in
Fig. 2. IGFBP-3-mediated VASP redistribution in human microvascular endothelial cells from the lungs (HMVEC-L). HMVEC-L, cultured on fibronectin-coated coverslips, were leftuntreated (A) or were treated with 100 ng/ml IGFBP-3 for 15 min (B) and Vasodilator-stimulated phosphoprotein (VASP) biodistribution was detected by immunofluorescence.IGFBP-3 treatment caused the rapid redistribution of VASP to the cells' periphery (A and B). C and D show, at higher magnification, a single cell in A and B, respectively. Notethe uniform VASP distribution throughout the cytoplasm along the actin filaments in the untreated sample (C) and the presence of VASP-free areas together with increasedVASP immunoreactivity along the plasma membrane in the IGFBP-3-treated cell, (D). Representative results from three independent experiments are shown. Green: VASP andblue: DAPI (for nuclear staining). (Scale bar = 25 m.)
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response to pro-angiogenic growth factors. Overexpression of IGFBP-5inhibitedVEGF-induced angiogenesis and inhibited both cell proliferationin human umbilical vein endothelial cells (HUVECs) and endothelial tubeformation [75]. IGFBP-5 also suppressed phosphorylation of eNOS, there-by inhibiting endothelial vasodilation suggesting an antagonistic effectwhen compared with IGFBP-3 [75]. IGFBP-4 on the other hand inhibitedfibroblast growth factor-2 and IGF-I induced angiogenesis in endothelialcells but had no effect in response to VEGF [76].
IGF-I has been shown to protect HRECs from apoptosis and enhanceproliferation, therefore abnormally high levels observed in the vitreoushumor may drive the progression of PDR [70]. Overexpression of IGF-Iimpaired functional recovery of acute ex vivo ischemic insult [77]. Ourprevious study disrupted IGF-IR and IGF-I binding using an IGF-IR ribo-zyme to investigate the interaction of IGF-I and retinopathy [43]. Thisribozyme, driven by a proliferating endothelial cell specific promoter,reduced pre-retinal neovascularization in both OIR and BVO models[43]. Widespread IGF-IR disruption through loss of norepinephrine,however, reduced IGF-IR phosphorylation and signaling which led toincreased apoptosis in the inner nuclear layers of the retina [78]. Simi-larly, long term diabetes have revealed increased IGFBP-3 expressionin human tears which can reduce IGF-IR phosphorylation and may beimplicated in the pathogenesis of ocular surface complications of thecornea [79].
Studies have established that PDR and accelerated neovascularizationis preceded by elevated IGF levels, however serum levels correlating tothe pathogenesis of PDR remain controversial [38,80–83]. Serum levelsof IGF-I was found to be decreased in retinopathy, nephropathy, andneuropathy [84–91]. However, another study examining patientswith either NPDR or PDR found no association of serum IGF-I in eitherinsulin-dependent or insulin-independent diabetes [92]. The differ-ences in these results may be due to sample size or patient character-istics and the methodology used to detect IGF-I [92]. Furthermoreserum levels may not be as relevant as localized increases in IGFs
and IGFBPs due to increased BRB permeability may be more relevantin PDR [52].
7. IGFBPs and proliferative vitreoretinopathy
Vascular injury or inflammation can lead to retinal detachmentfrom the basementmembranes of the eye. Proliferative vitreoretinopathy(PVR) is a fibrous scarring complication that is the leading cause in failureto treat rhegmatogenous retinal detachment [93–95]. Retinal tearingleads to fibrocellular scar formation at the vitreoretinal surface whichcontracts, pulling the retina away from the retinal pigment epithelium(RPE) [96]. Numerous studies have attributed RPE-derived cells in therole of retinal detachment as they are exposed to cytokines localizedto the vitreous [97–99]. Human RPE cells exhibited increased prolif-eration when exposed to basic fibroblast growth factor or epidermalgrowth factor, and the effect is enhanced under hypoxic condi-tions [100]. One study examined whether IGFBP-5 could inhibitN-(4-hydroxyphenyl)retinamide (4HPR) induced neuronal differenti-ation of human retinal pigment epithelial cells (ARPE-19). IGFBP-5 didnot inhibit transdifferentiation of ARPE-19, however, exogenous addi-tion of recombinant IGFBP-5 showed increased proliferation of RPEcells [21]. Thus, the expression of IGFBP-5 may stimulate proliferationand migration of RPE cells that can be fibrotic, leading to progressionof PVR [101].
Mukherjee et al. recently reported IGFBP expression patterns presentin several RPE progressive phenotypes: normal, early reactive, andmyofibroblastic [102]. IGFBP-1 was not detected, IGFBP-2 and IGFBP-4were expressed only in normal RPE, while IGFBP-3, IGFBP-5, andIGFBP-6 were found in all three phenotypes, with IGFBP-5 being pre-dominant in the myofibroblastic phenotype [102]. IGFBP-2 has beenshown to inhibit IGF-induced responses, therefore the loss of IGFBP-2in the early reactive phenotype may lead to increased growth factor ac-tivity and IGF mediated tractional force generation [99,103]. IGFBP-5
Fig. 3. General mechanism of vascular repair by IGFBP-3. CD34+ cells are recruited from the bone marrow by increased IGFBP-3 levels in the vasculature. IGFBP-3 binds to SR-B1,thereby leading to phosphorylation of eNOS and generating NO. IGFBP-3 can also mediate S1P generation by phosphorylating SphK-1, where S1P acts on its receptor to also stim-ulate phosphorylation of eNOS. NO stimulates a signaling cascade leading to VASP phosphorylation which is redistributed to polar ends of the cell and induces cell migration. Cellsmigrate to sites of injury to initiate capillary tube formation and vascular remodeling. IGFBP-3 can maintain tight and adherens junctions to maintain endothelium integrity as ob-served in the BRB.
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has also been shown to inducemigration of human lung fibroblasts andinduction of skin fibrosis, where migration of lung fibroblasts was viaIGF independent mechanisms [104,105]. Similarly, inflammation hasbeen linked to the pathogenesis of PVR, and IGFBP-5 has been shownto induce migration of mononuclear cells [104,106]. The presence ofIGFBP-5 in a fibrotic state in different cell types may suggest a functionof IGFBP-5 in mediating ocular fibrosis.
8. Hypertensive retinopathy
Long-term hypertension can potentially have similar retinal vascularpathology as observed in diabetic retinopathy. Association studies havefound that uncontrolled hypertensive patients with no diabetic compli-cations to be at higher risk of developing retinopathy [107]. 50–70% ofhypertensive patients were more likely to have retinal hemorrhages[107,108]. Plasma levels of IGF-I were found to be inversely associatedwith hypertension and both in vitro and in vivo experiments showedthat IGF-I decreases vascular resistance [109–111]. Groups have pro-posed a correlation of blood pressure to retinal microvascular changes,however the correlation decreases with age [107,109,112,113].
The regulation of IGFBP-3 levels may be influenced by standardtreatments for hypertension. Basic and clinical studies to date suggestIGFBP-3 to be vascular protective, however its effect on hypertensive
retinopathy is unclear. The ilSIRENTE study showed that older adultson angiotensin converting enzyme (ACE) inhibitors were found tohave significantly increased IGFBP-3 levels in serum, however therewas no significant association of ACE inhibitors with free IGF-I levels[114,115]. It may be that ACE inhibitor mechanism of action doesnot directly stimulate IGF-I activity to reduce vascular resistance,but rather works via increases in IGFBP-3 levels.
Retinal macroaneurysms can develop with complications of athero-sclerosis and hypertension in up to 75% patients andmanifests generallyin elderly [116,117]. IGFBP-7 has recently been linked to familial retinalarterial macroaneurysm (FRAM) [118]. FRAM may be due to reducedmechanical integrity of the arterial wall and individuals with FRAMwere found to have homozygous mutations in IGFBP-7 [118]. In situhybridization of retinal whole-mounts indicated that IGFBP-7 expres-sion was specific to the lens and retina in mouse embryos, howeverthe expression of IGFBP-7 has not been carried out in human eyes[118]. Additionally, hypertension has not yet been associated withinfluencing expression of IGFBP-7, however IGFBP-7 has been linkedto vascular function and endothelial-dependent vasodilation in high-ferritin insulin-dependent diabetes [119]. These findings reveal previ-ously unknown roles of the low affinity binding proteins to IGFs and indisease. One can speculate that IGFBP-7 may have other potentialfunctions in the pathogenesis of other retinopathies.
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9. Conclusion
Efforts in studying IGFBPs in recent years have identified an increas-ing role of IGFs and IGFBPs in ocular complications. IGFBP-3 appears tohave protective functions in the retina and BRB through stimulation andrecruitment of CD34+ cells, pericyte stability, and reducing inflamma-tion. However, the tissuemicroenvironment influences whether IGFBPshave stimulatory or inhibitory properties. The roles of IGFBP-5 in theRPE in PVR and IGFBP-7 in FRAMhave opened up the field to further in-vestigation. Future work should ascertain other regulatorymechanismsof the IGF system in ocular physiology and pathology.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This work was supported by the National Institutes of Health, R01EY007739, R01 EY12601, and R01 DK090730.
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