Review
VEGF: an update on biological and therapeutic aspects

https://doi.org/10.1016/S0958-1669(00)00153-1Get rights and content

Abstract

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and an angiogenic inducer as well as a mediator of vascular permeability. VEGF is essential for developmental angiogenesis and is also required for female reproductive functions and endochondral bone formation. Substantial evidence also implicates VEGF in tumors and intraocular neovascular syndromes. Currently, several clinical trials are ongoing to test the hypothesis that the inhibition of VEGF activity may be beneficial for these conditions.

Introduction

Over the past decade, extensive research has been done on members of the vascular endothelial growth factor (VEGF) gene family. There is strong evidence that this family plays a fundamental role in the growth and differentiation of vascular as well as lymphatic endothelial cells. This gene family comprises several members including VEGF, placenta growth factor, VEGF-B, VEGF-C, VEGF-D and two VEGF-like proteins encoded by two strains of the parapoxvirus orf virus [1], [2], [3]. In particular, VEGF [4], also referred to as VEGF-A, is a major regulator of normal and abnormal angiogenesis, including that associated with tumors and several intraocular syndromes [5], [6], [7]. VEGF inhibitors are currently being tested in a number of clinical trials [8]. Furthermore, VEGF is critical for the development of the vascular system: inactivation of even a single VEGF allele results in impaired angiogenesis and early embryonic lethality. For a comprehensive review of the molecular properties and clinical applications of VEGF and other members of the VEGF gene family, the reader is referred to several recent review articles [2], [3], [8], [9], [10], [11], [12], [13]. The purpose of this review is to provide an update on some aspects of the biology and clinical applications of VEGF-A and its inhibitors.

Section snippets

Biological actions of VEGF

VEGF was characterized as a mitogen for vascular endothelial cells derived from arteries, veins and lymphatics [1], [14], [15], [16]; however, recent studies have reported mitogenic effects of VEGF on a few non-endothelial cell types, such as retinal pigment epithelial cells [17], pancreatic duct cells [18] and Schwann cells [19]. There is strong evidence that VEGF is a key survival factor for endothelial cells, both in vitro and in vivo [20], [21], [22, [23]. Consistent with pro-survival

The VEGF receptor tyrosine kinases

Two VEGF receptor tyrosine kinases are known, Flt-1 (VEGF receptor [VEGFR]-1) [31], [32] and KDR (VEGFR-2) [33]. Gene targeting studies have demonstrated that both Flt-1 and KDR are essential for development of the embryonic vasculature in mice [34], [35]. There is compelling evidence that Flt-1 and KDR have different signal transduction properties and possibly mediate different functions [36], [37]. KDR undergoes strong ligand-dependent tyrosine phosphorylation in intact cells and mediated

Neuropilin-1 as a VEGF receptor: molecular analogies between axon guidance and angiogenesis

Soker et al. [45] have identified a receptor that binds VEGF165 but not VEGF121. This isoform-specific VEGF receptor is identical to neuropilin-1 (NRP1) [46], a receptor for the collapsin/semaphorin family that mediates neuronal cell guidance by providing a repulsive cue to sensory growth cones [47]. When coexpressed in cells with KDR, NRP1 enhanced the binding of VEGF165 to KDR and VEGF165-mediated chemotaxis. Conversely, inhibition of VEGF165 binding to NRP1 inhibits its binding to KDR and

VEGF is essential for embryonic and early postnatal development

In 1996, two studies generated direct evidence for the essential role of VEGF in embryonic vasculogenesis [53], [54]. Strikingly, targeted inactivation of a single VEGF allele in mice resulted in defective angiogenesis and embryonic lethality between day 11 and 12. An isoform-specific knockout of the VEGF gene has been also reported [55radical dotradical dot]. Fifty percent of the mice that exclusively express VEGF120 died shortly after delivery, whereas the remainder died within two weeks. The survivors

VEGF is required for endochondral bone formation

Endochondral bone formation is a fundamental mechanism for longitudinal bone growth during vertebrate development [59]. Recently, the role of VEGF in endochondral bone formation was examined. It has been shown that VEGF mRNA is expressed by hypertrophic chondrocytes in the epiphyseal growth plate [60, [61. Inhibition of VEGF activity using mFlt (1-3)IgG resulted in nearly complete suppression of blood vessel invasion, concomitant with impaired trabecular bone formation. Although proliferation,

Role of VEGF in the pathophysiology of the female reproductive tract

Follicular growth and the development and endocrine function of the ovarian corpus luteum (CL) are dependent on the proliferation of new capillary vessels [63]. Subsequently, the blood vessels regress, suggesting the coordinated action of inducers and inhibitors of angiogenesis in the course of the ovarian cycle [64], [65]. Previous studies have shown that VEGF mRNA is temporally and spatially related to the proliferation of blood vessels in the rat, mouse and primate ovary and in the rat

Role of VEGF in tumor and intraocular angiogenesis

There is compelling evidence that VEGF is a major tumor angiogenesis factor. The VEGF mRNA is upregulated in a large number of human tumor types (for reviews see [1], [27]). There is also a substantial body of data documenting that the inhibition of VEGF activity results in the suppression of growth of a wide variety of tumor cell lines in murine models [1], [2], [8]. A recent study has shown that combining an anti-Flk-1/KDR antibody with low-dose vinblastin results in a greater inhibitory

VEGF inhibition as a treatment for brain edema

Recently, van Bruggen et al. [101radical dotradical dot] tested the hypothesis that VEGF inhibition achieved by administration of mFlt (1-3)-IgG may have beneficial effects in cortical ischemia. Using high-resolution magnetic resonance imaging techniques to quantify the extent of the edematous changes, a significant reduction in the volume of the edematous tissue was observed one day following the onset of ischemia in a murine model; further, measurements of the resultant infarct size, measured several weeks later,

Conclusions and perspectives

The role of VEGF in developmental and pathological angiogenesis is well established. Yet, numerous fundamental questions remain to be fully answered, such as the significance of the Flt-1 receptor and its unconventional mode of action. The recent finding that key signaling functions in Flt-1 are constitutively inhibited by repressor motifs emphasizes the unique characteristics of this receptor [42radical dotradical dot]. In this context, an incompletely resolved issue is the significance of other members of the VEGF

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • radical dot of special interest

  • radical dotradical dot of outstanding interest

References (108)

  • BA Keyt et al.

    Identification of vascular endothelial growth factor determinants for binding KDR and FLT-1 receptors. Generation of receptor-selective VEGF variants by site-directed mutagenesis

    J Biol Chem

    (1996)
  • JE Park et al.

    Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR

    J Biol Chem

    (1994)
  • B Barleon et al.

    Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1

    Blood

    (1996)
  • S Soker et al.

    Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor

    Cell

    (1998)
  • H Fujisawa et al.

    Receptors for collapsin/semaphorins

    Curr Opin Neurobiol

    (1998)
  • Y Luo et al.

    Collapsin: a protein in brain that induces collapse and paralysis of neuronal growth cones

    Cell

    (1993)
  • BA Keyt et al.

    The carboxyl-terminal domain (111-165) of vascular endothelial growth factor is critical for its mitogenic potency

    J Biol Chem

    (1996)
  • HU Wang et al.

    Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4

    Cell

    (1998)
  • R Agrawal et al.

    Serum vascular endothelial growth factor and Doppler blood flow velocities in in vitro fertilization: relevance to ovarian hyperstimulation syndrome and polycystic ovaries

    Fertil Steril

    (1998)
  • P Salven et al.

    A high pretreatment serum vascular endothelial growth factor concentration is associated with poor outcome in non-Hodgkin's lymphoma

    Blood

    (1997)
  • MA Aboulghar et al.

    Elevated levels of interleukin-2, soluble interleukin-2 receptor alpha, interleukin-6, soluble interleukin-6 receptor and vascular endothelial growth factor in serum and ascitic fluid of patients with severe ovarian hyperstimulation syndrome

    Eur J Obstet Gynecol Reproduct Biol

    (1999)
  • Y Chen et al.

    Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen

    J Mol Biol

    (1999)
  • N Ferrara et al.

    The biology of vascular endothelial growth factor

    Endocr Rev

    (1997)
  • DW Leung et al.

    Vascular endothelial growth factor is a secreted angiogenic mitogen

    Science

    (1989)
  • KJ Kim et al.

    Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo

    Nature

    (1993)
  • LP Aiello et al.

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

    New Engl J Med

    (1994)
  • LP 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)
  • N Ferrara et al.

    Clinical applications of angiogenic growth factors and their inhibitors

    Nat Med

    (1999)
  • G Neufeld et al.

    Vascular endothelial growth factor (VEGF) and its receptors

    FASEB J

    (1999)
  • N Ortega et al.

    Signal relays in the VEGF system

    Front Biosci

    (1999)
  • B Olofsson et al.

    Current biology of VEGF-B and VEGF-C

    Curr Opin Biotechnol

    (1999)
  • T Veikkola et al.

    Regulation of angiogenesis via vascular endothelial growth factor receptors

    Cancer Res

    (2000)
  • P Carmeliet

    Mechanisms of angiogenesis and arteriogenesis

    Nat Med

    (2000)
  • G Conn et al.

    Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor

    Proc Natl Acad Sci USA

    (1990)
  • J Plouet et al.

    Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT20 cells

    EMBO J

    (1989)
  • M Guerrin et al.

    Vasculotropin/vascular endothelial growth factor is an autocrine growth factor for human retinal pigment epithelial cells cultured in vitro

    J Cell Physiol

    (1995)
  • M Sondell et al.

    Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system

    J Neurosci

    (1999)
  • T Alon et al.

    Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity

    Nat Med

    (1995)
  • LE Benjamin et al.

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

    J Clin Invest

    (1999)
  • F Yuan et al.

    Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody

    Proc Natl Acad Sci USA

    (1996)
  • DR Senger et al.

    Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid

    Science

    (1983)
  • HF Dvorak et al.

    Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis

    Am J Pathol

    (1995)
  • HF Dvorak

    Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing

    N Engl J Med

    (1986)
  • HF Dvorak et al.

    Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing

    Lab Invest

    (1987)
  • M Shibuya et al.

    Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase (flt) closely related to the fms family

    Oncogene

    (1990)
  • C de Vries et al.

    The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor

    Science

    (1992)
  • GH Fong et al.

    Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium

    Nature

    (1995)
  • F Shalaby et al.

    Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice

    Nature

    (1995)
  • L Seetharam et al.

    A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF

    Oncogene

    (1995)
  • S Hiratsuka et al.

    Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice

    Proc Natl Acad Sci USA

    (1998)
  • Cited by (0)

    View full text