ReviewVEGF: an update on biological and therapeutic aspects
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 [55]. 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. [101] 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 [42]. 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:
of special interest
of outstanding interest
References (108)
Role of vascular endothelial growth factor in the regulation of angiogenesis
Kidney Int
(1999)- et al.
Signaling angiogenesis and lymphangiogenesis
Curr Opin Cell Biol
(1998) - et al.
Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells
Biochem Biophys Res Commun
(1989) - et al.
Effects of vascular endothelial growth factor on pancreatic duct cell replication and the insulin production of fetal islet-like cell clusters in vitro
Mol Cell Endocrinol
(1997) - et al.
Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells
J Biol Chem
(1998) - et al.
VEGF regulates endothelial cell survival by the PI3-kinase/Akt signal transduction pathway: requirement for Flk-1/KDR activation
J Biol Chem
(1998) - et al.
Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis
Cell
(1999) - et al.
Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability
Mol Cell
(1999) - et al.
Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor
Biochem Biophys Res Commun
(1992) - et al.
Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor
J Biol Chem
(1994)
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
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
Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1
Blood
Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor
Cell
Receptors for collapsin/semaphorins
Curr Opin Neurobiol
Collapsin: a protein in brain that induces collapse and paralysis of neuronal growth cones
Cell
The carboxyl-terminal domain (111-165) of vascular endothelial growth factor is critical for its mitogenic potency
J Biol Chem
Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4
Cell
Serum vascular endothelial growth factor and Doppler blood flow velocities in in vitro fertilization: relevance to ovarian hyperstimulation syndrome and polycystic ovaries
Fertil Steril
A high pretreatment serum vascular endothelial growth factor concentration is associated with poor outcome in non-Hodgkin's lymphoma
Blood
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
Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinity-matured Fab in complex with antigen
J Mol Biol
The biology of vascular endothelial growth factor
Endocr Rev
Vascular endothelial growth factor is a secreted angiogenic mitogen
Science
Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo
Nature
Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders
New Engl J Med
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
Clinical applications of angiogenic growth factors and their inhibitors
Nat Med
Vascular endothelial growth factor (VEGF) and its receptors
FASEB J
Signal relays in the VEGF system
Front Biosci
Current biology of VEGF-B and VEGF-C
Curr Opin Biotechnol
Regulation of angiogenesis via vascular endothelial growth factor receptors
Cancer Res
Mechanisms of angiogenesis and arteriogenesis
Nat Med
Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor
Proc Natl Acad Sci USA
Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT20 cells
EMBO J
Vasculotropin/vascular endothelial growth factor is an autocrine growth factor for human retinal pigment epithelial cells cultured in vitro
J Cell Physiol
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
Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity
Nat Med
Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal
J Clin Invest
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
Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid
Science
Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis
Am J Pathol
Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing
N Engl J Med
Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing
Lab Invest
Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase (flt) closely related to the fms family
Oncogene
The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor
Science
Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium
Nature
Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice
Nature
A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF
Oncogene
Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice
Proc Natl Acad Sci USA
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