Vascular endothelial growth factors and angiogenesis in eye disease☆
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)
- et al.
Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy
Am. J. Ophthalmol.
(1994) - et al.
Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors
J. Biol. Chem.
(1999) Retinal vascularization in health and disease
Am. J. Ophthalmol.
(1957)Oxygen and the growth and development of retinal vessels. In vivo and in vitro studies. The XX Francis I. Proctor Lecture
Am. J. Ophthalmol.
(1966)- et al.
Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1
Blood
(1996) - et al.
Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris
Evidence for a trophic paracrine relation. Am. J. Pathol.
(1999) - et al.
Vascular development and disordersmolecular analysis and pathogenic insights
Kidney Int.
(1998) - et al.
Endothelium-derived agents in pericyte function/dysfunction
Prog. Retina Eye Res.
(1999) - et al.
Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus
Lancet
(1998) - et al.
Upregulation of vascular endothelial growth factor by angiotensin II in rat heart endothelial cells
Bioch. Biophys. Acta
(1998)
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.
Aldose reductasea window to the treatment of diabetic complications?
Prog. Retina Eye Res.
Role of the pericyte in wound healing. An ultrastructural study
Exp. Mol. Pathol.
The role of VEGF and thrombospondins in skin angiogenesis
J. Dermatol. Sci.
Ischemia-driven angiogenesis
Trends Cardiovasc. Med.
VEGF regulates cell behavior during vasculogenesis
Dev. Biol.
Requirements for binding and signaling of the kinase domain receptor for vascular endothelial growth factor
J. Biol. Chem.
Unbalanced expression of VEGF and PEDF in ischemia-induced retinal neovascularization
FEBS Lett.
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.
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.
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.
Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells
J. Biol. Chem.
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.
Hepatocyte growth factor/scatter factor in the eye
Prog. Retina Eye Res.
Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis
Cell
Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids
Lab. Invest.
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
Inhibition of vascular endothelial growth factor prevents retinal ischemia-associated iris neovascularization in a nonhuman primate
Arch. Ophthalmol.
Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders
N. Engl. J. Med.
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
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
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
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.
Renal renin-angiotensin system in diabetesfunctional, immunohistochemical, and molecular biological correlations
Am. J. Physiol.
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
Molecular mechanisms of vascular permeability in diabetic retinopathy
Semin. Ophthalmol.
The absence of diabetic retinopathy in patients with retinitis pigmentosaimplications for pathophysiology and possible treatment
Br. J. Ophthalmol.
Evidence for pigment epithelium-derived factor receptors in the neural retina
Invest. Ophthalmol. Vis. Sci.
Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia
Circ. Res.
Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal
J. Clin. Invest.
VEGF localisation in diabetic retinopathy
Br. J. Ophthalmol.
Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation
Development
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.
Retinal and choroidal neovascularization
J. Cell. Physiol.
The pathogenesis of choroidal neovascularization in patients with age- related macular degeneration
Mol. Vis.
In vivo angiogenic activity and hypoxia induction of heterodimers of placenta growth factor/vascular endothelial growth factor
J. Clin. Invest.
Vascular endothelial growth factor C induces angiogenesis in vivo
Proc. Natl. Acad. Sci. USA
Mechanisms of angiogenesis and arteriogenesis
Nat. Med.
Role of vascular endothelial growth factor and vascular endothelial growth factor receptors in vascular development
Curr. Top. Microbiol. Immunol.
Angiogenesis in cancer and other diseases
Nature
Cited by (0)
- ☆
Supported by: Haagsch Oogheelkundig Fonds, Edmond and Marianne Blaauwfonds, and Landelijke Stichting voor Blinden en Slechtzienden.