The role of vascular endothelial growth factor and other endogenous interplayers in age-related macular degeneration

doi:10.1016/j.preteyeres.2008.05.002

Progress in Retinal and Eye Research

Volume 27, Issue 4, July 2008, Pages 372-390

https://doi.org/10.1016/j.preteyeres.2008.05.002 Get rights and content

Abstract

Age-related macular degeneration (AMD) is a multifaceted disease characterized by early subclinical changes at the choroidea–retinal pigment epithelium interface. Both the causal and formal pathogenesis of the disease is still puzzling. Similarly, the reason for progression into two distinct late forms which are “geographic atrophy” and “choroidal neovascularization” remains enigmatic. Late changes are usually responsible for the dramatic loss in central function that has a devastating effect on quality of life.

In industrialized countries the disease is a major cause for visual disability among persons over 60 years of age. Due to demographic right-shift and increased life expectancy, AMD is not only a medical problem but will have a pronounced socio-economic effect.

Neovascular AMD with the development of choroidal neovascularization in the macular area accounts for 80% of the severe loss of visual acuity due to AMD. In the last decades, treatment modes were merely based on the destruction or surgical removal of the neovascular complex. In the present, however, the philosophical approach to treat the disease is changing to a pathology modifying manner. Intelligent targeting of the involved relevant factors and pathways should stop disease progression, reduce complications and improve vision. The first step into this new era has been accomplished with the introduction of antiangiogenic agents. The new agents act either directly on vascular endothelial growth factor (VEGF) or indirectly on its functional cascade.

VEGF makes a fundamental contribution to neovascular processes but it also acts in physiological pathways. The main purpose of this review is to summarize its physiological role especially within the eye, the role in the development of AMD and to understand and foresee both the benefits and potential side-effects of the anti-VEGF-based therapy.

Section snippets

Age-related macular degeneration (AMD)

AMD is a complex multistage disease ranging from early subclinical alterations at the choroidea–retinal pigment epithelium (RPE) interface to advanced atrophic or fibrovascular changes associated with a degenerated and functionally inactive central retina. Genetic predisposition (Klaver et al., 1998; Meyers et al., 1995; Hammond et al., 2002; Tuo et al., 2004; Traboulsi, 2005), dietary and environmental risk factors contribute to the development of the disease, but changes due to aging may well

Neovascularization and VEGF

Neovascularization as seen in CNV is the development of new vessels and can be roughly classified into two ways. Vasculogenesis is the establishment of a new vascular network from hematopoietic precursor cells that differentiate into endothelial cells (ECs). Angiogenesis describes the sprouting of new vessels from existing ones. This process is associated with changes in EC activity and intercellular adhesions (Dvorak et al., 1995; Roberts and Palade, 1995). The vessel becomes more permeable

VEGF in the development of choroidal neovascularization

The development of CNV, the hallmark of neovascular AMD, is a complex and multifactorial process. However, CNV is not restricted to AMD and has been described in more than 30 distinct ocular diseases such as angioid streaks, myopia, trauma, ocular histoplasmosis, Sorsby fundus dystrophy and multifocal choroiditis (Green and Wilson, 1986) It is therefore to be assumed that disease-specific mechanisms may initiate CNV development; however, the process itself is a non-specific wound-healing

Summary and future directions

Experimental studies demonstrating that blocking of VEGF or its signaling cascade suppresses CNV (Krzystolik et al., 2002) led to the prediction that VEGF antagonists might provide benefit in patients with exudative AMD. The proof of concept was delivered by clinical studies showing that intravitreal administration of a VEGF antagonist ameliorated the visual outcome as compared with sham injections (Gragoudas et al., 2004; Brown et al., 2006; Rosenfeld et al., 2006). The succesful introduction

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Anti-VEGF-based treatment have been regularly used in recent years in proliferative diabetic retinopathy (PDR) patients. However, some of these patients fail to respond effectively to anti-VEGF. Given that VEGF is not the sole factor influencing PDR pathogenesis and that different anti-VEGF pharmaceuticals are likely to differentially impact these underlying pathophysiological processes, we performed a prospective analysis of the protein profiles of the aqueous humor (AH) in PDR patients before and after treatment with three intravitreal anti-VEGF drugs (ranibizumab, aflibercept, and conbercept) to assess and compare the short-term impacts of these agents. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic methods were used to evaluate the AH protein profiles of PDR patients using paired pre- and 7 days post-anti-VEGF treatment samples (ranibizumab [IVR]: n = 10; conbercept [IVC]: n = 10; aflibercept [IVA]: n = 5). Gene ontology (GO) annotation, KEGG pathway analyses, and protein-protein interaction (PPI) networks were then used to explore the functional relevance of proteins that were differentially expressed between groups. Here, a total of 874 proteins from 25 patients (50 AH samples) were identified in the three patient groups. Different and common clusters of regulated proteins for each group were identified. We identified RARRES1, ALDH3A1, and RBP4 as being specifically regulated following treatment with all three tested anti-VEGF agents. We further found that VEGFR1, VEGFR2, APOM, hornerin, and HSP90B1 were differentially expressed in different anti-VEGF agent groups. In summary, we discovered that ALDH3A1 was a previously unreported protein that was related to angiogenesis and was differentially expressed in the three anti-VEGF treatment groups, suggesting that it may be a new target for PDR therapy. The described proteomic changes in the AH of PDR patients treated with different anti-VEGF agents provide novel targets which may explain the heterogeneity of anti-VEGF treatment responses in these patients, providing a robust foundation for future studies of PDR pathogenesis.
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Sub-RPE drusen and damage to BM in AMD create a pro-inflammatory and pro-angiogenic environment that increases the risk of CNV formation(Grisanti and Tatar, 2008; Guymer et al., 1999; Nozaki et al., 2006). The formation of type 1 (i.e. ‘occult’) sub-RPE neovascular tissue (CNV-1) can further damage the RPE and may lead to SRF leakage through the resulting dysfunctional RPE outer blood-retina barrier(Anderson et al., 2010; Bergen et al., 2019; Curcio, 2018; Grisanti and Tatar, 2008; Guymer et al., 1999; Nozaki et al., 2006). Several other diseases such as high myopia, angioid streaks, multifocal choroiditis, and choroidal rupture can also be complicated by serous SRF in the macula as a result of CNV.
A wide range of ocular diseases can present with serous subretinal fluid in the macula and therefore clinically mimic central serous chorioretinopathy (CSC). In this manuscript, we categorise the diseases and conditions that are part of the differential diagnosis into 12 main pathogenic subgroups: neovascular diseases, vitelliform lesions, inflammatory diseases, ocular tumours, haematological malignancies, paraneoplastic syndromes, genetic diseases, ocular developmental anomalies, medication-related conditions and toxicity-related diseases, rhegmatogenous retinal detachment and tractional retinal detachment, retinal vascular diseases, and miscellaneous diseases. In addition, we describe 2 new clinical pictures associated with macular subretinal fluid accumulation, namely serous maculopathy with absence of retinal pigment epithelium (SMARPE) and serous maculopathy due to aspecific choroidopathy (SMACH). Differentiating between these various diseases and CSC can be challenging, and obtaining the correct diagnosis can have immediate therapeutic and prognostic consequences. Here, we describe the key differential diagnostic features of each disease within this clinical spectrum, including representative case examples. Moreover, we discuss the pathogenesis of each disease in order to facilitate the differentiation from typical CSC.
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And recruited macrophages by several chemokines are believed to contribute to the development of CNV by producing TNF-α and other cytokines that regulate angiogenesis (Cousins, Espinosa-Heidmann, & Csaky, 2004). MMP-2 and MMP-9 are proteolytic enzymes which specifically degrade collagens in extracelllular matrix (ECM), increasing the bioavailability of VEGF since ECM proteins sequester VEGF and other growth factors (Grisanti & Tatar, 2008; Lambert et al., 2003). The released VEGF by RPE stimulates angiogenesis by increasing endothelial proliferation (Vadlapatla, Vadlapudi, Pal, Mukherji, & Mitra, 2014) which leads to development of CNV.
Accumulation of N-retinylidene-N-retinylethanolamine (A2E) and light exposure are known to be intensely involved in the progression of age-related macular degeneration (AMD). It has been demonstrated that when A2E was exposed to light, oxidative byproducts of A2E (oxo-A2E) are generated, causing cell death. We aimed to investigate the effects of quercetin-3-O-α-l-arabinopyranoside (QA) on ultraviolet A (UVA) exposure in human retinal pigment epithelial cells (ARPE-19 cells) and retinas of balb/c mice. This study demonstrated that QA inhibited translocation of NF-kB and upregulations of inflammatory related genes such as IL-1β, IL-6, MCP-1, CXCL-2, and VEGF-A, significantly increased by UVA exposure. In addition, QA prevented UVA induced apoptosis through decreasing caspase 3 activation and PARP cleavage both in APRE-19 cells and in retinas. Taken together, our study demonstrated the protective effects of QA on UVA induced apoptosis, suggesting that QA could be a potential agent to prevent onset and progression of AMD.

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The role of vascular endothelial growth factor and other endogenous interplayers in age-related macular degeneration

Abstract

Section snippets

Age-related macular degeneration (AMD)

Neovascularization and VEGF

VEGF in the development of choroidal neovascularization

Summary and future directions

Biochem. Biophys. Res. Commun.

Surv. Ophthalmol.

Biochim. Biophys. Acta

Am. J. Ophthalmol.

Am. J. Ophthalmol.

Mol. Ther.

Surv. Ophthalmol.

Exp. Eye Res.

Am. J. Pathol.

J. Biol. Chem.

J. Biol. Chem.

Prog. Retin. Eye Res.

Ophthalmology

FEBS Lett.

Am. J. Ophthalmol.

Biochem. Biophys. Res. Commun.

FEBS Lett.

Am. J. Ophthalmol.

Am. J. Ophthalmol.

Am. J. Ophthalmol.

Ophthalmology

Ophthalmology

Exp. Eye Res.

Am. J. Ophthalmol.

Am. J. Ophthalmol.

Ophthalmology

Exp. Cell. Res.

Am. J. Ophthalmol.

Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects

Cancer Res.

Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4)

Proc. Natl. Acad. Sci. USA

Related Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate

Arch. Ophthalmol.

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

Requirement for vascular endothelial growth factor in wound- and inflammation-related corneal neovascularization

Invest. Ophthalmol. Vis. Sci.

Growth factor localization in choroidal neovascular membranes of age-related macular degeneration

Invest. Ophthalmol. Vis. Sci.

Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb

J. Clin. Invest.

EIAV vector-mediated delivery of endostatin or angiostatin inhibits angiogenesis and vascular hyperpermeability in experimental CNV

Gene Ther.

VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma

Cancer Res.

In vivo angiogenic activity of interleukins

Arch. Ophthalmol.

Reduced choroidal neovascular membrane formation in matrix metalloproteinase-2-deficient mice

Invest. Ophthalmol. Vis. Sci.

Localization of collagen XVIII and the endostatin portion of collagen XVIII in aged human control eyes and eyes with age-related macular degeneration

Invest. Ophthalmol Vis. Sci.

Evidence for an inflammatory process in age-related macular degeneration gains new support

Proc. Natl. Acad. Sci. USA

Role of complement and complement attack complex in laser-induced choroidal neovascularization

J. Immunol.

Photodynamic therapy with verteporfin (Visudyne): impact on ophthalmology and visual sciences

Invest. Ophthalmol. Vis. Sci.

Clinicopathological correlation of drusen and retinal pigment epithelial abnormalities in age-related macular degeneration

Retina

ANCHOR Study Group, Ranibizumab versus verteporfin for neovascular age-related macular degeneration

N. Engl. J. Med.

Retinal and choroidal neovascularization

J. Cell Physiol.

Ocular neovascularization and excessive vascular permeability

Expert. Opin. Biol. Ther.

Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele

Nature

Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocytes procoagulant activity, and promotes monocyte migration

J. Exp. Med.

Tumor vascular permeability factor stimulates endothelial cell growth andangiogenesis

J. Clin. Invest.