Vascular endothelial growth factors and angiogenesis in eye disease

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Abstract

The vascular endothelial growth factor (VEGF) family of growth factors controls pathological angiogenesis and increased vascular permeability in important eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). The purpose of this review is to develop new insights into the cell biology of VEGFs and vascular cells in angiogenesis and vascular leakage in general, and to provide the rationale and possible pitfalls of inhibition of VEGFs as a therapy for ocular disease. From the literature it is clear that overexpression of VEGFs and their receptors VEGFR-1, VEGFR-2 and VEGFR-3 is causing increased microvascular permeability and angiogenesis in eye conditions such as DR and AMD. When we focus on the VEGF receptors, recent findings suggest a role of VEGFR-1 as a functional receptor for placenta growth factor (PlGF) and vascular endothelial growth factor-A (VEGF)-A in pericytes and vascular smooth muscle cells in vivo rather than in endothelial cells, and strongly suggest involvement of pericytes in early phases of angiogenesis. In addition, the evidence pointing to distinct functions of VEGFs in physiology in and outside the vasculature is reviewed. The cellular distribution of VEGFR-1, VEGFR-2 and VEGFR-3 suggests various specific functions of the VEGF family in normal retina, both in the retinal vasculature and in neuronal elements. Furthermore, we focus on recent findings that VEGFs secreted by epithelia, including the retinal pigment epithelium (RPE), are likely to mediate paracrine vascular survival signals for adjacent endothelia. In the choroid, derailment of this paracrine relation and overexpression of VEGF-A by RPE may explain the pathogenesis of subretinal neovascularisation in AMD. On the other hand, this paracrine relation and other physiological functions of VEGFs may be endangered by therapeutic VEGF inhibition, as is currently used in several clinical trials in DR and AMD.

Introduction

Neovascularisation in the eye is associated with various disorders, often causing severe loss of vision and eventually blindness. Among these disorders, diabetic retinopathy (DR) and age-related macular degeneration (AMD) are the most prevalent in the Western World. In the United States, approximately 8% of the persons between 20 and 72, who are legally blind, have DR due to diabetes mellitus (DM) as a cause of their blindness (Klein et al., 1989). AMD is the major cause of loss of vision in persons older than 65 with over 55,000 patients suffering from this disease in the Netherlands alone (La Heij et al., 2001). For both diseases, adequate therapy is not available to date. Laser photocoagulation therapy is performed to physically destroy new vessels in AMD, or to decrease vascular leakage and stop the process of neovascularisation in DR, although the mechanisms underlying these effects are not known. Laser treatment can be painful, it permanently damages the retina with local visual field loss and is often ineffective on the medium or long term. Therefore, new therapeutic approaches are sought for these conditions. Characterisation of the different processes involved in the pathogenesis of DR and AMD is a prerequisite to develop therapies to treat and eventually to prevent loss of vision and blindness. Vascular endothelial growth factor-A (VEGF-A) is a protein involved in the onset and progression of both DR and AMD. Theoretically, this makes VEGF and its signalling receptors potential targets for pharmaceutical intervention. Clinical application of anti-VEGF therapies has reached phase II/III trials. Recent findings on VEGFs and their receptors are reviewed here, especially in relation to eye diseases, as well as possible implications of these findings for therapeutic strategies.

Section snippets

Angiogenesis and lymphangiogenesis

In healthy adults, the vasculature is quiescent except during wound healing (Paavonen et al., 2000; Ruiter et al., 1993), hair growth (Yano et al., 2001) and the menstrual cycle (Ferrara et al., 1998). Otherwise, endothelial cells show very little proliferation (Engerman et al., 1967). Imbalance in the demand and supply of oxygen and nutrients, as occurs in the course of, for instance, proliferative DR, tumour growth, or myocardial infarction, results in sprouting of new capillaries from

The vascular endothelial growth factor (VEGFs) family

The vascular endothelial growth factor family includes placenta growth factor (PlGF), VEGF-A, VEGF-B, VEGF-C, VEGF-D and the viral VEGF homologue VEGF-E (Fig. 2; Eriksson and Alitalo, 1999; Ferrara, 1999; Persico et al., 1999; Olofsson et al., 1998). VEGF-A, which has been studied most extensively, is a dimeric 36–46 kd glycosylated protein with a N-terminal signal sequence and a heparin-binding domain. In the human, four different VEGF-A isoforms have been identified with varying numbers of

VEGF receptors

Three members of the VEGFR family have been identified so far. Two high-affinity receptor tyrosine kinases have been identified for VEGF-A, namely VEGFR-1 (fms-like tyrosine kinase-1 or Flt-1) and VEGFR-2 (kinase insert domain-containing receptor or KDR). The third high-affinity receptor VEGFR-3 (fms-like tyrosine kinase-4 or Flt-4) is a receptor for VEGF-C and VEGF-D (Joukov et al., 1996). VEGF-C and VEGF-D also bind to VEGFR-2, but with a lower affinity than they bind to VEGFR-3 (Achen et

Embryo

The development of vasculature is a fundamental requirement in organ development and differentiation during embryogenesis. Vascular development from the haemangioblast stage up to the stage of a complex vascular network is characterised by different phases. In each of these phases, VEGF-A is suggested to play an important role, a notion supported by in vitro and in vivo studies (reviewed in Carmeliet and Collen, 1999). Targeted inactivation of a single allele of the VEGF-A gene in mice causes

VEGFs and VEGFRs in pathology

In the last decade, it has become clear that VEGF-A plays a predominant role in the development of pathological angiogenesis as occurs in cancer and in ischaemic and inflammatory diseases (Yancopoulos et al., 2000; Carmeliet and Jain, 2000). VEGF-A mRNA levels are upregulated in a large number of clinical and experimental tumours (Yancopoulos et al., 2000; Carmeliet and Jain, 2000; Ferrara and Davis-Smyth, 1997; Dvorak et al., 1995). In addition, VEGF-A protein is present in synovial fluid in

VEGFs and VEGFRs in the normal eye

The retina in the eye has a dual vascular supply (Fig. 7, Fig. 8). A delicate network of retinal vessels feeds the inner layers of the retina. The outer retina, in which photoreceptors are located, is avascular and depends on the extensively fenestrated capillary plexus of the adjacent choroid (choriocapillaris). Retinal vascular endothelial cells have tight junctions and form the inner blood–retinal barrier, which means that transport from the blood to the interstitium is highly restricted and

Non-proliferative diabetic retinopathy (NPDR)

A variety of metabolic imbalances and vascular changes, such as thickening of the basement membrane, apoptosis of pericytes and endothelial cells and diffusely increased vascular permeability, occur in the retina in DM, long before DR is clinically recognised. It is well established that hyperglycaemia is a major risk factor for the development and progression of DR (Klein et al., 1998). The retina is one of the few tissues, which does not require insulin to transport glucose into the cell.

VEGF- and VEGFR-based anti-angiogenic therapies: future directions

In 1971, Folkman hypothesised that growth of tumours is angiogenesis-dependent and that anti-angiogenic therapy may represent an option for the treatment of solid tumours. Since then, numerous reports have pointed at the crucial role of neovascularisation in malignancy and various non-neoplastic diseases, including DR and AMD.

Understanding the steps in the angiogenic processes and the angiogenic factors involved in angiogenesis has led to the development of targeting strategies for new agents

References (248)

  • M Clauss et al.

    The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis

    J. Biol. Chem.

    (1996)
  • M.J Crabbe et al.

    Aldose reductasea window to the treatment of diabetic complications?

    Prog. Retina Eye Res.

    (1998)
  • D.J Crocker et al.

    Role of the pericyte in wound healing. An ultrastructural study

    Exp. Mol. Pathol.

    (1970)
  • M Detmar

    The role of VEGF and thrombospondins in skin angiogenesis

    J. Dermatol. Sci.

    (2000)
  • Y Dor et al.

    Ischemia-driven angiogenesis

    Trends Cardiovasc. Med.

    (1997)
  • C.J Drake et al.

    VEGF regulates cell behavior during vasculogenesis

    Dev. Biol.

    (2000)
  • G Fuh et al.

    Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor

    J. Biol. Chem.

    (1998)
  • G Gao et al.

    Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization

    FEBS Lett.

    (2001)
  • G Gao et al.

    Down-regulation of vascular endothelial growth factor and up-regulation of pigment epithelium-derived factora possible mechanism for the anti-angiogenic activity of plasminogen kringle 5

    J. Biol. Chem.

    (2002)
  • H.P Gerber et al.

    Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia

    J. Biol. Chem.

    (1997)
  • H.P Gerber et al.

    Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation

    J. Biol. Chem.

    (1998)
  • H.P Gerber et al.

    Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells

    J. Biol. Chem.

    (1998)
  • H Gille et al.

    Analysis of Biological Effects and Signaling Properties of Flt-1 (VEGFR- 1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants

    J. Biol. Chem.

    (2001)
  • I Grierson et al.

    Hepatocyte growth factor/scatter factor in the eye

    Prog. Retina Eye Res.

    (2000)
  • D Hanahan et al.

    Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis

    Cell

    (1996)
  • C Hornig et al.

    Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids

    Lab. Invest.

    (2000)
  • M.G Achen et al.

    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. US A

    (1998)
  • A.P Adamis et al.

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

    Arch. Ophthalmol.

    (1996)
  • L.P Aiello et al.

    Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders

    N. Engl. J. Med.

    (1994)
  • L.P Aiello et al.

    Identification of multiple genes in bovine retinal pericytes altered by exposure to elevated levels of glucose by using mRNA differential display

    Proc. Natl. Acad. Sci. USA

    (1994)
  • L.P Aiello et al.

    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)
  • L.P Aiello et al.

    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)
  • R.H Amin et al.

    Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy

    Invest. Ophthalmol. Vis. Sci.

    (1997)
  • S Anderson et al.

    Renal renin-angiotensin system in diabetesfunctional, immunohistochemical, and molecular biological correlations

    Am. J. Physiol.

    (1993)
  • D.A Antonetti et al.

    Vascular permeability in experimental diabetes is associated with reduced endothelial occludin contentvascular endothelial growth factor decreases occludin in retinal endothelial cells

    Penn State Retina Research Group. Diabetes

    (1998)
  • D.A Antonetti et al.

    Molecular mechanisms of vascular permeability in diabetic retinopathy

    Semin. Ophthalmol.

    (1999)
  • G.B Arden

    The absence of diabetic retinopathy in patients with retinitis pigmentosaimplications for pathophysiology and possible treatment

    Br. J. Ophthalmol.

    (2001)
  • M.S Aymerich et al.

    Evidence for pigment epithelium-derived factor receptors in the neural retina

    Invest. Ophthalmol. Vis. Sci.

    (2001)
  • D Bellomo et al.

    Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia

    Circ. Res.

    (2000)
  • L.E Benjamin et al.

    Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal

    J. Clin. Invest.

    (1999)
  • M Boulton et al.

    VEGF localisation in diabetic retinopathy

    Br. J. Ophthalmol.

    (1998)
  • G Breier et al.

    Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation

    Development

    (1992)
  • C.P Burren et al.

    Localization of mRNAs for insulin-like growth factor-I (IGF-I), IGF-I receptor, and IGF binding proteins in rat eye

    Invest. Ophthalmol. Vis. Sci.

    (1996)
  • P.A Campochiaro

    Retinal and choroidal neovascularization

    J. Cell. Physiol.

    (2000)
  • P.A Campochiaro et al.

    The pathogenesis of choroidal neovascularization in patients with age- related macular degeneration

    Mol. Vis.

    (1999)
  • Y Cao et al.

    In vivo angiogenic activity and hypoxia induction of heterodimers of placenta growth factor/vascular endothelial growth factor

    J. Clin. Invest.

    (1996)
  • Y Cao et al.

    Vascular endothelial growth factor C induces angiogenesis in vivo

    Proc. Natl. Acad. Sci. USA

    (1998)
  • P Carmeliet

    Mechanisms of angiogenesis and arteriogenesis

    Nat. Med.

    (2000)
  • P Carmeliet et al.

    Role of vascular endothelial growth factor and vascular endothelial growth factor receptors in vascular development

    Curr. Top. Microbiol. Immunol.

    (1999)
  • P Carmeliet et al.

    Angiogenesis in cancer and other diseases

    Nature

    (2000)
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    Supported by: Haagsch Oogheelkundig Fonds, Edmond and Marianne Blaauwfonds, and Landelijke Stichting voor Blinden en Slechtzienden.

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