Growth Factors, Receptors, and Extracellular Matrix Molecules: Key Factors in Controlling Normal and Abnormal Growth of Ocular Tissues

EGFR and Uveal Melanoma

Expression of epidermal growth factor receptor (EGFR), a transmembrane glycoprotein, has been shown to be an indicator of poor prognosis in various malignancies. Binding of EGFR can induce cell differentiation, proliferation, and the expression of oncogenes. In the present study, Hurks et al. (p. 2023) demonstrate that in human uveal melanoma, EGFR expression is significantly correlated with death due to metastatic disease. Therefore, EGFR expression can be regarded as an important prognostic factor in human uveal melanoma and may be a promising target for the development of new therapeutic strategies. 

VEGF and Proliferative Retinopathy

Patients with proliferative diabetic retinopathy demonstrate elevated plasma levels of vascular endothelial growth factor (VEGF) and von Willebrand factor (vWf). Lip et al. (p. 2115) found no difference in levels of sFlt-1, a soluble VEGF receptor, between patients and controls. Following successful laser treatment, plasma VEGF levels decreased significantly at 4 months’ follow-up, but there were no significant changes in plasma sFlt-1 or vWf concentrations. Monitoring levels of plasma VEGF may provide an opportunity for monitoring disease progression or relapse and the efficacy of therapeutic interventions via a blood sample. 

MMPs and Pterygium Fibroblasts

Matrix metalloproteinases (MMPs) are associated with connective tissue degradation, fibrovascular proliferation, and angiogenesis. In this study, Solomon et al. (p. 2154) show that cultured pterygium fibroblasts overexpress certain MMPs in response to inflammatory cytokines such as IL-1β and TNF-α. These data imply an inflammatory component in the pathogenesis and progression of pterygia. Anti-inflammatory agents in conjunction with pterygium surgery may be of benefit by downregulating the expression of MMPs in pterygium fibroblasts. 

EGF and Corneal Epithelial Growth

Epidermal growth factor (EGF) stimulates corneal epithelial proliferation. Kang et al. (p. 2164) show that this response is due to the stimulation of two parallel cell signaling pathways linked to EGF receptor (EGFR) stimulation: 1) the mitogen-activated protein kinase (MAPK) cascade, which maximally promotes cell growth; and 2) a prostaglandin (PGE₂) linked pathway, ultimately mediating increases in protein kinase A (PKA) activity. Such increases in PKA activity dampen EGF-induced Raf-1 activation as a negative feedback regulation. Therefore, the mitogenic response to EGF actually reflects cross-talk between these two signaling pathways, indicating a regulatory mechanism of corneal epithelial cell growth. 

TM-ECM in Glaucoma

Why is there increased extracellular matrix (ECM) material in the trabecular meshwork (TM) of glaucomatous eyes? It has been proposed that this is due to increased synthesis of ECM, or to decreased synthesis of ECM-degrading enzymes. The study of Welge-Lüßen et al. (p. 2229) provides evidence for a new mechanism. The authors show that human TM synthesizes tissue transglutaminase (tTgase), an enzyme forming intra-ECM cross-links resistant to enzymatic degradation. The data further show that treatment of human TM cells with TGF-β increases expression of tTgase and fibronectin, and that extracellular tTgase irreversibly cross-links fibronectin. Such changes have potentially important implications for aqueous humor drainage in normal and glaucomatous eyes. 

GAGs and TM Outflow

Brimonidine, a highly selective and potentα ₂-adrenoceptor agonist, is emerging as a first-line therapy for primary open-angle glaucoma. Its ability to suppress aqueous secretion is well-documented; however, effects on aqueous outflow are unknown. Benozzi et al. (p. 2268) demonstrate that brimonidine activates α₂-adrenoceptors in the rabbit TM and significantly increases hyaluronidase activity via a cyclic AMP-independent mechanism. These data suggest that hypotensive effects of brimonidine are in part mediated by an ability to decrease outflow resistance in the TM by increasing the catabolism of glycosaminoglycans (GAGs). 

Bradykinin and Glutamate Toxicity

Yasuyoshi et al. (p. 2273) have shown that bradykinin (BK)-B2 receptor immunoreactivity is widely distributed in rat retina and that cultured retinal neurons express BK-B2 receptor mRNA. Furthermore, BK has a protective action against glutamate neurotoxicity via BK-B2 receptors in cultured retinal neurons. The protective action is suggested to occur downstream to nitric oxide (NO) synthesis and presumed to involve some process related to oxygen radical formation in glutamate neurotoxicity. Although this protective effect has only thus far been demonstrated in vitro, the results suggest a possible therapeutic strategy for treating retinal dysfunction associated with glutamate neurotoxicity. 

Endothelin and Smooth Muscle Contraction

Endothelin is an important mediator of vascular smooth muscle contraction. Part of its action is thought to result from the activation of Ca²⁺-dependent Cl⁻- currents that depolarize the membrane and subsequently cause increased Ca²⁺ influx through voltage-operated Ca²⁺ channels (VOCCs). Curtis and Scholfield (p. 2279) show that in choroidal arteriolar smooth muscle, endothelin evokes transient inward Ca²⁺-activated Cl⁻-currents induced through the cyclical release and re-uptake of Ca²⁺ from intracellular stores following ET_A receptor stimulation. Paradoxically, these currents may be more important in limiting Ca²⁺ influx through store-refilling channels than increasing influx through VOCCs, which are negatively coupled to the ET_A receptors. 

PPAR-γ and CNV

Novel pharmacologic therapies for choroidal neovascularization (CNV) complicating age-related macular degeneration are urgently needed. Thiazolidinediones (TZDs) are a novel class of drugs that are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-γ. In this study, Murata et al. (p. 2309) show that synthetic TZDs inhibit VEGF-induced angiogenesis in vitro and laser-induced CNV in a rat model. These drugs are currently widely prescribed for the treatment of noninsulin-dependent diabetes mellitus and should be investigated further for their use in the treatment of CNV and efficacy in inhibiting the development of proliferative diabetic retinopathy. 

PAI-1 and Diabetic Retinopathy

Basement membrane thickening, a hallmark of early diabetic retinopathy, may arise from increased deposition or decreased proteolysis. Plasminogen activator inhibitor (PAI)-1, the major regulator of fibrinolysis overexpressed by individuals with diabetes, contributes to thickening by inhibiting proteolysis. Grant et al. (p. 2296) examined the role of PAI-1 in ocular changes using a transgenic mouse model overexpressing human PAI-1. After 20–49 weeks, basement membranes from retinal capillaries were thickened significantly in transgenics compared to controls. Retinas also demonstrated pericyte loss. PAI-1 overexpression, independent of other metabolic changes resulting from diabetes, is thus sufficient to induce retinal vascular changes seen early in diabetic retinopathy. 

Somatostatin Receptors and CNV

The growth of neovascularization beneath the macula is regulated by a myriad of stimulating and inhibiting growth factors. Somatostatin affects ocular angiogenesis by inhibiting the growth hormone-insulin-like growth factor axis and also has a direct antiproliferative effect on human retinal endothelial cells. Lambooij et al. (p. 2329) showed that somatostatin receptor subtype 2A (sst_2A) is expressed strongly in most newly formed endothelial cells of choroidal neovascular (CNV) membranes secondary to age-related macular degeneration (AMD). sst_2A receptors bind potential anti-angiogenic somatostatin analogues such as octreotide. Thus, somatostatin analogues might be of therapeutic interest for early stages of CNV in AMD. 

FGF Receptors and RPE Differentiation

RPE cells undergo dedifferentiation as part of the development of proliferative diseases of the posterior pole, such as proliferative vitreoretinopathy and age-related macular degeneration. In this study, Alizadeh et al. (p. 2357) demonstrate that both the relative expression of fibroblast growth factor (FGF) receptor genes and the alternative splicing of FGF mRNAs are regulated by differentiation and dedifferentiation of RPE cells. Dedifferentiation of ARPE-19 cells has been accompanied with a shift in alternative splicing of FGFR1α to FGFR1β. This observation suggests that undifferentiated RPE cells in vivo may be more responsive to FGF2 than differentiated RPE cells. 

BDNF and Ganglion Cell Survival

Kashiwagi et al. (p. 2373) studied the effects of brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-4 on retinal ganglion cells (RGCs) isolated and cultured in a serum-free medium using flow cytometry. This technique can evaluate a larger number of cells in a shorter period of time. The study shows that BDNF improved the survival rate of RGCs, particularly of small RGCs, in a concentration-dependent fashion. NT-4 had little influence on the survival rate of RGCs. The method is useful in evaluating the effects of neuroprotective factors or neurotoxic factors on cultured RGCs. 

TSP-1 and Ocular Angiogenesis

Thrombospondin (TSP)-1 is a large (450 kDa) extracellular matrix glycoprotein that has been reported to be both anti- and proangiogenic in various models. These conflicting results may be due to the complex structure of the protein and its ability to interact with several different receptors on the same cell type. Shafiee et al. (p. 2378) used small peptides (less than 20 amino acids) derived from TSP-1 and synthetic peptide analogues to show that two subdomains of this protein independently influenced angiogenesis in a retinal explant assay and a rat model of retinopathy of prematurity (ROP). A tryptophan-rich, heparin-binding sequence inhibited endothelial cell growth in the explant assay and neovascular pathology in the rat ROP model. This study demonstrated that agents competing with heparin-binding growth factors for cell surface heparan sulfate proteoglycans may be promising pharmacological agents for treatment of ocular angiogenesis. 

VEGF Receptors and PVR

Strategies to kill pathologic RPE cells in nonvascular epiretinal membranes from patients with proliferative vitreoretinopathy (PVR) are required. Hoffmann et al. (p. 2389) exploit the increased expression of vascular endothelial growth factor (VEGF) receptors on TGF-β–activated RPE to target these cells using a VEGF-diphtheria toxin conjugate. This study demonstrates for the first time the ability to target nonendothelial cells by means of VEGF receptor expression. In vivo experiments are now required to determine whether the toxin is safe for intraocular administration and whether selective killing of RPE can be achieved in a PVR model.