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a Department of Biology, Technion, Israel Institute of Technology, Technion City, Haifa 32000, Israel
| ABSTRACT |
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Key Words: hypoxia angiogenesis oncogene heparan-sulfate proteoglycan cytokine
| OVERVIEW OF EARLY STUDIES |
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These initial discoveries were followed by the identification of specific VEGF receptors, first at the level of binding/cross-linking studies (7, 8) and then by identification of the VEGFR-1 (flt-1) and VEGFR-2 (KDR/flk-1) genes that encode VEGF specific tyrosine-kinase receptors. These receptors are characterized by the presence of seven immunoglobulin-like domains in their extracellular parts and can therefore be regarded as a new subfamily of tyrosine-kinase receptors (9, 10) (
Fig. 1).
Important advances were also made regarding the biological role of VEGF. It was discovered that VEGF is expressed in spatial and temporal association with physiological events of angiogenesis in vivo (11, 12). Inhibition of VEGF activity by neutralizing antibodies or by the introduction of dominant negative VEGF receptors into endothelial cells of tumor-associated blood vessels resulted in the inhibition of tumor growth and in tumor regression, indicating that VEGF is a major initiator of tumor angiogenesis (13, 14). Furthermore, it was found that VEGF expression is potentiated by hypoxia and that the potentiation of VEGF production in hypoxic areas of solid tumors contributes significantly to VEGF-driven tumor angiogenesis (15, 16). VEGF-induced angiogenesis was also found to play an important role in the etiology of several additional diseases associated with abnormal angiogenesis (17, 18) and in wound repair (19).
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These advances were accompanied by the identification of additional growth factors belonging to the VEGF family that share common receptors with VEGF. The discovery of placenta growth factor (PlGF) (20) was followed by the recent discovery of three additional growth factors belonging to the VEGF family (VEGF B-D) and by the discovery of an additional receptor (VEGFR-3) belonging to the VEGF receptor family. A summary of the interactions of the VEGF family growth factors with the various VEGF receptors is presented in
Fig. 1. However, because of space limitations, this review does not cover the biology of these VEGF-related factors except when such studies relate directly to VEGF. The reader will find additional information regarding these growth factors in recent reviews (21, 22). Studies that have concentrated on the role of VEGF in embryonic development are covered partially for similar reasons. These studies are also covered in greater depth in recent reviews (2325).
| THE ROLE OF VEGF AND ITS RECEPTORS IN VASCULOGENESIS AND ANGIOGENESIS |
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The role of VEGF in the early development of the vasculature
The importance of VEGF as a central regulator of vasculogenesis was demonstrated in studies that have used the technique of targeted gene disruption in mice. Even animals that lack one of the two VEGF alleles die before birth because of defects in the development of the cardiovascular system (26, 27). These observations indicate that the development of the cardiovascular system depends on the generation of precise VEGF concentration gradients and that a decrease in the amounts of the VEGF produced during the development of the embryo may lead to decreased angiogenesis with fatal consequences. Likewise, disruption of the genes encoding the VEGF tyrosine-kinase receptors VEGFR-2 (28) and VEGFR-1 (29) results in severe abnormalities of blood vessel formation in homozygous animals. Embryos lacking the VEGFR-2 gene die before birth because differentiation of endothelial cells does not take place and blood vessels do not form (28). A recent study has indicated that VEGFR-2 is required for the differentiation of endothelial cells and for the movement of primitive precursors of endothelial cells from the posterior primitive streak to the yolk sac, a precondition for the subsequent formation of blood vessels (30). Disruption of the gene encoding the VEGFR-1 receptor did not prevent the differentiation of endothelial cells in homozygous animals, but the development of functional blood vessels from these endothelial cells was severely impaired (29). Activation of the VEGFR-1 receptor promotes cell migration but does not seem to induce cell proliferation efficiently (31, 32). It is thus possible that decreased cell migration or defects in endothelial cellcell or cellmatrix interactions result in the defective organization of blood vessels in mice lacking functional VEGFR-1 (29).
Hypoxia-driven retinal angiogenesis as a model for the role of angiogenesis during organ development
Hypoxia-induced VEGF production may provide the driving force that stimulates the angiogenesis that accompanies organ formation during development. Perhaps the best-studied example of such an event is the development of the retina and the associated network of retinal blood vessels. The picture that has emerged from the retina studies may also be true for the development of vascular systems in other organs. As the retina develops, astrocytes and neuronal precursors spread out and migrate away from the existing blood vessels. As the distance between the astrocytes and the existing vasculature increases, the astrocytes encounter progressively increasing hypoxic conditions. The astrocytes are more sensitive to hypoxia than the comigrating neuronal cells, and thus serve as hypoxia sensors. The hypoxia stimulates the astrocytes to produce VEGF, and the VEGF sets in motion an angiogenic response (33, 34). A VEGF concentration gradient is formed that stimulates the growth of new blood vessels toward the VEGF-producing astrocytes. The result is that growing blood vessels follow the astrocytes that continue to migrate outward. As the hypoxic pressures ease after the arrival of the blood vessels, the production of VEGF by the astrocytes decreases. However, a certain threshold concentration of VEGF is required to inhibit apoptosis of the endothelial cells and is essential for the stabilization of the newly formed blood vessels. The falling levels of VEGF cause disassembly of some of these vessels, leaving intact a vascular network that is finely tuned to respond to the demands of the organ (35). The remaining vessels are later stabilized and rendered insensitive to VEGF withdrawal by pericytes that follow in the wake of the endothelial cells to cover the newly formed blood vessels (36).
Deregulated VEGF production results in angiogenic diseases of the retina
When cells lose the ability to control the synthesis of VEGF for any number of reasons, angiogenic disease ensues. In retinopathy of prematurity babies are placed in hyperoxygenated incubators because their lungs are not yet fully developed. This causes the astrocytes that are the sensors of hypoxia during the development of the retina to decrease VEGF production, causing newly formed blood vessels to regress and halting the orderly process of retinal angiogenesis during retina development. When the babies are moved out of the incubators, all the cells in the retina suddenly experience extreme hypoxia and produce simultaneously large amounts of VEGF. This overproduction results in rampant angiogenesis, which is not as finely choreographed as the angiogenesis that takes place during normal retinal development. The ensuing deregulated growth of blood vessels is the cause of blindness in babies that have been subjected to such treatment (37, 38). A similar sequence of events can also be seen in other types of retinopathies in which partial or general ischemia of the retina is accompanied by overexpression of VEGF and hyperproliferation of blood vessels leading to blindness (17, 18, 39, 40). This model is also supported by recent experiments that have demonstrated hyperproliferation of blood vessels in transgenic mice engineered to overproduce VEGF in retinal cells (41).
When tissues are exposed to high concentrations of VEGF, additional abnormalities besides the hyperproliferation of blood vessels can be observed. Newly formed blood vessels of quail embryos exposed to high concentrations of VEGF undergo unregulated and excessive fusion of vessels that results in the formation of vessels with abnormally large lumens. This unregulated fusion leads in extreme cases to the formation of fused vascular sacs that obliterate the identity of individual vessels (42). If, in contrast, the VEGF supply is reduced or completely inhibited, the result is impaired angiogenesis, which can lead to the inhibition of organ development. A truncated soluble VEGFR-1 was used to inhibit angiogenesis during the development of the corpus luteum in a rat model of hormonally induced ovulation. The inhibition of angiogenesis resulted in the complete inhibition of corpus luteum development (43). These experiments support the hypothesis that the availability of angiogenic factors such as VEGF may be a major limiting factor that controls the extent of organ development and growth (44).
The role of VEGF in tumor angiogenesis
Even though tumors are composed of dedifferentiated cells and do not exhibit an organized structure, from the point of view of angiogenesis a growing tumor may be viewed as a developing new organ. Angiogenesis is as essential for the growing tumor as it is for a developing organ such as the corpus luteum, since the delivery of blood-borne nutrients to the tumor cells is essential for their survival (43, 45). Therefore the production of angiogenic factors by tumorigenic cells is essential for the development of solid tumors (46). Initial studies have revealed that when VEGF signaling is inhibited, tumor angiogenesis and, consequently, tumor growth are impaired (13, 14). VEGF also contributes to the development of tumors because of its ability to induce permeabilization of blood vessels. VEGF induces the formation of fenestrations in blood vessels (47, 48) and the formation of vesiculo-vacuolar organelles that form channels through which blood-borne proteins can extravasate (49). This leads to the formation of an extravascular fibrin gel, which provides a matrix that supports the growth of endothelial cells and tumor cells and allows invasion of stromal cells into the developing tumor (50).
In many types of tumors, elevated levels of VEGF production can often be detected in tumor cells located at the extreme periphery of the tumor where there is no hypoxia. It was subsequently observed that activated oncogenes that are part of the ras/MAP-kinase signal transduction pathway potentiate VEGF mRNA expression (51, 52). Hypoxia-independent production of VEGF by tumorigenic cells can also be brought about by the inactivation of tumor suppressors such as p53 (53, 54) or by exogenous factors such as hormones or growth factors (55). The molecular mechanisms by which these inducers affect VEGF production in normal and tumor cells are discussed in greater detail in the section dealing with the regulation of VEGF production.
As tumors expand, the cells within the expanding mass of the tumor are frequently deprived of oxygen because their distance from the nearest blood vessels increases. This results in the generation of hypoxic regions within tumors; the tumorigenic cells within these hypoxic areas respond by the stimulation of VEGF production, which then triggers angiogenesis using mechanisms similar to the mechanisms by which astrocytes sense hypoxia and induce angiogenesis in the developing retina. This results in particularly high levels of VEGF expression in hypoxic regions, which are usually located near necrotic areas within tumors (56). The generality of this mechanism of VEGF induction explains why VEGF seems to be involved in the induction of tumor angiogenesis in so many types of diverse tumors. Another VEGF-related mechanism by which tumor angiogenesis can be induced involves production of VEGF-like proteins by viruses. The AIDS virus protein, HIV-1/Tat, can bind and activate VEGFR-2 (57). This probably represents a mechanism by which the AIDS virus enhances the angiogenic stimuli provided by Kaposi sarcoma herpes virus-encoded proteins (58), contributing to the development of Kaposi sarcoma in AIDS patients.
The use of VEGF and VEGF function inhibitors as drugs for various diseases associated with angiogenic disorders
The initial studies indicating that inhibition of VEGF signal transduction can inhibit tumor progression (13, 14) were followed by studies that have indicated that inhibition of VEGF signaling inhibits the development of many types of tumors (59). Recent studies also suggest that inhibition of VEGF function abrogates tumor metastasis, possibly because the tumor cells come into contact with a lesser concentration of blood vessels (60). These observations have sparked intense efforts directed at the development of efficient inhibitors of VEGF production and VEGF signal transduction for anti-tumorigenic purposes. Efforts to inhibit VEGF-induced tumor angiogenesis include the development of humanized neutralizing anti-VEGF monoclonal antibodies (61), inhibitory soluble VEGF receptors (43, 62, 63), antisense VEGF mRNA expressing constructs (64, 65), VEGF-toxin conjugates (66), antagonistic VEGF mutants (67), and inhibitors of VEGF receptor function (60, 68, 69). All these strategies hold promise, and it remains to be seen whether one of these approaches will lead to the development of an efficient inhibitor of VEGF-induced tumor angiogenesis.
The angiogenic properties of VEGF have also been exploited recently to induce in vivo angiogenesis for the treatment of two types of diseases associated with impaired blood supply. In some cases, VEGF was delivered to the sites of interest as a protein (70). In other cases expression plasmids containing the VEGF cDNA or recombinant viruses were used in a gene therapy approach (7173). Successful attempts aimed at induction of collateral blood vessels in ischemic heart disease, critical limb ischemia, and reendothelialization by VEGF have been reported recently (70, 7476), and efforts are continuing.
| THE REGULATION OF VEGF PRODUCTION |
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(79), transforming growth factor ß (TGF-ß) (80), keratinocyte growth factor (KGF) (81), IGF-I (82), interleukin 1ß (IL-1ß) (83), and IL-6 (84). Other cytokines such as IL-10 and IL-13 can inhibit the release of VEGF (85). An interesting example illustrating the complexity of the regulation of VEGF production during a biological process is the regulation of VEGF production during dermal wound healing. The expression of KGF is strongly potentiated during wound repair (86). KGF, in turn, induces VEGF production in keratinocytes. In addition, hydrogen peroxide, a VEGF-inactivating oxidant (87) produced by neutrophils that invade the wound as part of the healing process, also potentiates VEGF production by keratinocytes (88). The production of VEGF in keratinocytes is also strongly induced by UV-B radiation, again as part of a wound repair mechanism that involves angiogenesis (88). Another small molecule that up-regulates VEGF expression is nitric oxide. Nitric oxide contributes to the blood vessel-permeabilizing effects of VEGF and to VEGF-stimulated vasodilatation (8991). The production of nitric oxide is in turn up-regulated by VEGF, indicating that a positive feedback loop exists between these two factors (92, 93).
The mechanism by which hypoxia regulates VEGF production
Hypoxia and hypoglycemia are major stimulators of VEGF expression (15). The production of other VEGF family members such as VEGF-B, VEGF-C, and PlGF does not seem to be potentiated by hypoxia even though some of these factors such as VEGF-C are strong angiogenic factors in their own right (94, 95). The mechanisms that regulate VEGF production by oxygen availability have therefore received particular attention in recent years and are slowly being worked out. The mechanisms responsible for induction of VEGF and erythropoietin expression are similar (96). Hypoxia-induced transcription of VEGF mRNA is apparently mediated, at least in part, by the binding of hypoxia-inducible factor 1 (HIF-1) to an HIF-1 binding site located in the VEGF promoter (97, 98). It turns out that some mechanisms that lead to elevated VEGF production independently of hypoxia actually short-circuit the normal hypoxia sensing mechanism that regulates VEGF expression. For example, it was observed that the oncogene v-src can induce expression of HIF-1, thereby short-circuiting the HIF-1-dependent hypoxia sensing mechanism and leading to increased expression of VEGF (99). Several additional HIF-1-like factors regulate VEGF production, but these transcription factors are not as well characterized (100, 101). In addition to the induction of transcription, hypoxia promotes the stabilization of the VEGF mRNA by proteins that bind to sequences located in the 3' untranslated region (UTR) of the VEGF mRNA (102104). Recently, one such protein has been identified as the HuR mRNA binding protein (105). It is clear that additional proteins stabilize the VEGF mRNA, but their identity is still unknown.
Recent evidence indicates that the hypoxia-mediated elevation in VEGF transcription is also mediated by sites that are found in the 5' untranslated region of the VEGF mRNA (UTR), which is particularly long. The 5' UTR contains an alternative transcription initiation site and an active internal ribosomal entry site (IRES) located downstream of this alternative initiation site. MRNA initiated from this alternative start site contains the IRES. The translation of such uncapped mRNA is probably regulated primarily by the IRES and may be advantageous under conditions in which cap-dependent translation is inhibited, as is the case under stressful conditions such as the conditions prevailing during hypoxia (106, 107).
Regulation of VEGF expression by the von Hippel-Landau (vHL) and p53 genes
Inactivation of tumor suppressors is an additional mechanism that leads to overexpression of VEGF in tumor cells. Cerebellar hemangioblastomas and human renal carcinomas are highly vascular, nonnecrotic, and presumably nonhypoxic tumors producing high levels of VEGF. Cells derived from such tumors contain mutations in the gene encoding the vHL tumor suppressor gene (108). This observation suggest that mutations in the vHL gene are associated with increased angiogenesis, and it was indeed found that cells from such tumors display increased VEGF expression as a result of the inactivation of vHL (109, 110). Wild-type vHL inhibits the production of several hypoxia-regulated proteins such as the GLUT-1 glucose transporter gene in addition to VEGF. vHL inhibition of VEGF expression is mediated by transcriptional and posttranscriptional mechanisms (111, 112). At the posttranscriptional level, vHL inhibits the activity of protein kinase C zeta and delta (113). In the absence of wild-type vHL, these kinases are active and the VEGF mRNA is stabilized as a result of the constitutive interaction of several proteins that are normally induced by hypoxia with a 500 base region in the 3' UTR (54). At the transcriptional level, vHL forms a complex with the Sp1 transcription factor and inhibits SP1-mediated VEGF expression as a result of the binding of SP1 to a specific region in the VEGF promoter (111). These Sp1 binding sites are also important for PDGF-induced VEGF expression; mutations that inhibit Sp1 binding also abolish PDGF-induced VEGF expression (78). The expression of PDGF-BB is also potentiated by hypoxia (114).
Another tumor suppressor associated with the control of VEGF expression seems to be P53. The loss of the wild-type P53 is associated with increased angiogenesis in developing tumors (115). Wild-type P53 was identified as an inhibitor of VEGF production (116), and mutated P53 was observed to potentiate VEGF expression (53). However, a recent report apparently contradicts these findings and indicates that wild-type P53 may not function as an inhibitor of VEGF expression (117).
| THE VEGF SPLICE VARIANTS AND THE ROLE OF CELL-SURFACE HEPARAN-SULFATE PROTEOGLYCANS |
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The interaction between VEGF and cell-surface heparan-sulfates and its role
The heparin binding forms of VEGF can bind to cell-surface and extracellular matrix-associated heparan-sulfate proteoglycans and can release angiogenic factors such as bFGF, which are stored on heparan-sulfates of the extracellular matrix (130). This observation is significant because VEGF and bFGF synergize with respect to their ability to induce angiogenesis (131). Extracellular matrix-associated heparans-sulfate proteoglycans may also function as an extracellular storage place for the heparin binding VEGF isoforms (121). Heparan-sulfate proteoglycans regulate the interaction of several heparin binding growth factors with their respective receptors and, consequently, their biological activity (132). Early experiments have indicated that the binding of 125I-VEGF165 to endothelial cell-surface receptors such as VEGFR-2 can be strongly enhanced by heparin (133). However, subsequent experiments have shown that heparin-like molecules do not potentiate significantly the binding of native VEGF165 to VEGFR-2. Oxidized VEGF165 and VEGF121 lose their ability to bind to VEGFR-2. Cell-surface heparan-sulfate proteoglycans such as glypican (134) fulfill a chaperone-like role and can restore the VEGFR-2 binding ability of oxidized VEGF165 (S. Gengrinovitch, unpublished results). In contrast, the VEGFR-2 binding ability of VEGF121 cannot be restored by heparan-sulfate proteoglycans after oxidative damage (87). This observation may explain why VEGF121 was reported to be much less potent than VEGF165 by some researchers (135), whereas others report smaller differences in activity (87, 136). It is possible that VEGFs sustain various degrees of damage during their purification from cells or bacteria expressing recombinant VEGF and that such damage can be readily detected in the case of VEGF121, because cell-surface heparan-sulfates do not restore the activity of such damaged VEGF121.
Several studies indicate that heparan-sulfates may bind to VEGF receptors such as VEGFR-2 and regulate their VEGF165 binding ability (137, 138). However, the binding of VEGF121 to VEGFR-2 is not affected by heparin or heparan-sulfate proteoglycans, indicating that heparan-sulfates probably cannot modulate the VEGF121 binding ability of this particular receptor (87). However, the VEGF121 binding ability of other types of VEGF receptors may be directly affected by heparan-sulfates (122).
| THE VEGF RECEPTORS |
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The expression of VEGFR-2 and VEGFR-1 was reported to be affected by hypoxia, although to a lesser extent than that of VEGF. The transcription of VEGFR-1, but not that of VEGFR-2, is enhanced by hypoxia (151). VEGFR-2 production is also up-regulated under hypoxic conditions, but the mechanism responsible for the induction seems to be posttranscriptional (152). This hypoxia-induced change in VEGFR-2 and VEGFR-1 expression may be triggered indirectly, since VEGF potentiates the expression of both receptor types (153, 154).
The interaction of VEGF with VEGFR-1 and VEGFR-2
Two separate domains of VEGF interact with VEGFR-2 and VEGFR-1. Alanine-scanning mutagenesis has revealed that Arg(82), Lys(84), and His(86), are critical for the binding of VEGF to VEGFR-2, while Asp(63), Glu(64), and Glu(67) are required for the binding of VEGF to VEGFR-1. These binding domains are located at opposite ends of the VEGF monomer. In the mature VEGF dimer, the monomers are linked in a rough `head-to-tail' fashion (with a large overlap) by disulfide bridges so that the main VEGFR-2 binding domains are at opposite ends of the molecule, as are the main VEGFR-1 binding domains (
Fig. 2 A, B)
Fig. 2).
(155, 156). This spatial arrangement is in agreement with observations indicating that mutations within the VEGFR-2 binding site of VEGF have a minimal effect on the binding of VEGF to VEGFR-1, and that mutants affecting the VEGFR-1 binding site of VEGF do not affect the binding of VEGF to VEGFR-2 (155). Furthermore, mutated VEGF deficient in VEGFR-2 binding ability did not induce proliferation of endothelial cells, whereas mutants deficient in their VEGFR-1 binding ability were still able to induce endothelial cell proliferation (155). Nevertheless there is considerable overlap in the binding domains that interact with VEGFR-1 and VEGFR-2 at the groove formed between the VEGF monomers with which both VEGF receptors interact (
Fig. 2A, B) (157). The arrangement of the receptor binding sites on VEGF indicates that a VEGF dimer may be able to bind and link together two VEGF receptors to form signaling homo- or heterodimers of receptors (
Fig. 2C) (157, 158). Indeed, there is some evidence indicating that VEGFR-2 and VEGFR-1 can form heterodimers after VEGF binding (159). In the case of VEGFR-1, it was recently determined that the VEGF binding site is located in the second and third immunoglobulin-like loops and that two VEGFR-1 receptors can be linked by a VEGF bridge (157). It was also determined that the fourth immunoglobulin-like loop contains a receptor dimerization domain (157, 160162) (
Fig. 1). The second and the third immunoglobulin-like loops of VEGFR-2 are also sufficient for VEGF binding (158); its fourth immunoglobulin-like loop may also function as a dimerization domain, although there is no experimental data as yet to prove that assumption. The c-kit receptor that belongs to the PDGF subfamily of tyrosine-kinase receptors contains five immunoglobulin-like domains (as compared to seven in VEGF receptors). This receptor also possesses a dimerization domain located in its fourth immunoglobulin-like loop and a ligand binding site in the second and third immunoglobulin-like loops (163). These structural similarities indicate that the VEGF and PDGF tyrosine-kinase receptor subfamilies are evolutionarily linked; this assumption was strengthened by a study that compared the structure of VEGFR-1 with the structure of several receptors belonging to the PDGF receptor family (164).
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Biological responses mediated by the activation of VEGFR-1 and VEGFR-2
Activation of the VEGFR-2 receptor by VEGF in cells devoid of VEGFR-1 results in a mitogenic response, while the activation of VEGFR-1 by VEGF in cells lacking VEGFR-2 does not induce cell proliferation (32, 165). However, activation of VEGFR-1 by VEGF does induce cell migration, a response that is also induced as a result of VEGFR-2 activation by VEGF (31, 166, 167). These results indicate that the signal transduction cascades induced by VEGFR-1 and VEGFR-2 are somewhat different. The information regarding the signaling cascades induced by each of these receptors is limited, and it is not yet completely clear why VEGFR-1 does not induce cell proliferation in response to VEGF and VEGFR-2 does. VEGF promoted the binding and phosphorylation of the Shc and Nyc adapters, Grb-2 binding, and MAP kinase activation in porcine aortic endothelial cells expressing recombinant VEGFR-2. In contrast, MAP kinase was not activated by VEGF in cells expressing recombinant VEGFR-1 in two separate studies (32, 168). It is therefore possible that VEGFR-1 does not induce cell proliferation, because it does not activate MAP kinase. The SHP-1 and SHP-2 SH2 protein-tyrosine phosphatases physically associate with VEGFR-2 after stimulation with VEGF, raising the interesting possibility that both molecules participate in the modulation of VEGF-induced signals (168). Eventually, activation of the VEGF receptors results in the generation of proteases that are required for the breakdown of the basement membrane of blood vessels in the first steps of angiogenesis (169171), in the expression of specific integrins required for angiogenesis (172), and, finally, in the initiation of cell proliferation and cell migration.
The VEGF165-specific receptor neuropilin-1
Endothelial cells also contain VEGF receptors possessing a lower mass than either VEGFR-2 or VEGFR-1 (133). It was subsequently found that these smaller VEGF receptors of the endothelial cells are isoform specific and bind to VEGF165, but not to VEGF121. It was therefore recognized that these receptors are not related to the VEGFR-1 or VEGFR-2 receptors that bind to both VEGF isoforms (87). It was previously observed that several types of nonendothelial cells express these VEGF165-specific receptors (133), and an additional search revealed several types of prostate and breast cancer cell lines that express unusually large amounts of these isoform-specific receptors (173). The binding of VEGF165 to these receptors is apparently mediated by amino acids residing at the carboxyl-terminal part of the exon 7-encoded peptide of VEGF165 (173, 174). The genes encoding these receptors were identified by using a combination of VEGF165 affinity chromatography and expression cloning. The affinity purification approach revealed that the receptors seen in breast cancer MDA-MB-231 cells are encoded by neuropilin-1 (167), a receptor previously identified as a receptor for several types of semaphorins. Semaphorins were initially characterized as factors that act as repellents of nerve growth cones (175, 176). In addition, the expression cloning approach has led to the identification of another VEGF165 receptor, which turned out to be the product of the closely related gene, neuropilin-2 (167, 175). It was recently observed that neuropilin-1 also functions as a receptor for the heparin binding form of PlGF, PlGF-2, but not for PlGF-1 (177).
The neuropilins have a short intracellular domain (
Fig. 1) and are therefore unlikely to function as independent receptors. Indeed, no responses to VEGF165 were observed when cells expressing neuropilin-1 but no other VEGF receptors were stimulated with VEGF165 (167). Nevertheless, gene disruption studies indicate that neuropilin-1 is probably an important regulator of blood vessel development as mouse embryos lacking a functional neuropilin-1 gene die because their cardiovascular system fails to develop properly (178). It is therefore likely that neuropilin-1 is a VEGF165 coreceptor. This assumption is supported by experiments showing that VEGFR-2 binds VEGF165 more efficiently in cells expressing neuropilin-1, and that this potentiating effect is subsequently translated into a better migratory response to VEGF165 as compared to the migratory response of cells expressing VEGFR-2 but no neuropilin-1 (167). In contrast, PlGF-1 and PlGF-2 potentiated the migration of endothelial cells equally well. This observation may indicate that neuropilin-1 is not able to function as a VEGFR-1 coreceptor, since PlGF was reported to induce cell migration via activation of the VEGFR-1 receptor (177, 179).
The identification of neuropilin-1 as a coreceptor of VEGFR-2 may explain why the cardiovascular system of neuropilin-1 -/- embryos fails to develop normally (178). The identification of neuropilin-1 as a coreceptor of VEGFR-2 may provide an alternative explanation as to why VEGF121, a VEGF splice variant that does not bind to neuropilin-1, seems to be a less active mitogen than VEGF165. However, it should be pointed out that the measured differences between the mitogenic activities of VEGF121 and VEGF165 are divergent in different studies because of unknown reasons (119, 136). The identification of neuropilins as VEGF165 receptors also suggests that the different semaphorins may play a role in angiogenesis by interacting with neuropilins expressed in endothelial cells and, conversely, that VEGF165 may activate neuropilin receptors of neuronal cells. Additional isoform-specific VEGF receptors may also exist, as suggested by a study in which a different VEGF165-specific receptor was described (180). However, the gene encoding this receptor has not yet been identified.
| CONCLUSIONS AND FUTURE DIRECTIONS |
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The research conducted after the discovery of VEGF revealed that VEGF is a central regulator of angiogenesis and vasculogenesis. Several diseases, such as cancer, are characterized by abnormal angiogenesis, and it was realized that in many cases these diseases are accompanied by the aberrant production of VEGF. Moreover, it was realized that modulation of VEGF function may contribute to a successful therapeutic treatment of these diseases. However, at the moment VEGF signal transduction is not sufficiently understood. It is therefore likely that the study of VEGF signal transduction will be an area of intensive investigation in the near future. Research aimed at the elucidation of the mechanisms that fine-tune VEGF production is also likely to be at the center of attention. The understanding of these processes is essential for the successful development of methods aimed at the modulation of VEGF-induced angiogenesis.
VEGF and the VEGF family members represent but one set of proteins of a whole set of regulatory factors acting in concert to shape networks of mature, functional blood vessels (181). There are indications that different angiogenic factors such as bFGF and VEGF may promote angiogenesis by using subtly different mechanisms (172). It is thus reasonable to assume that a major research effort will be concentrated in the future on the mechanisms by which the activity of different angiogenic and anti-angiogenic factors is coordinated. These future research efforts should lead to a better understanding of angiogenesis and, consequently, to the development of better drugs aimed at the treatment of diseases associated with angiogenic disorders.
| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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2 Abbreviations: bFGF, basic fibroblast growth factor; HIF-1, hypoxia-inducible factor 1; IL, interleukin; IRES, internal ribosomal entry site; PDGF, platelet-derived growth factor; PlGF, placenta growth factor; KGF, keratinocyte growth factor; TGF, transforming growth factor; UTR, untranslated region; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; vHL, von Hippel-Landau; VPF, vascular permeability factor. ![]()
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K. R. Swanson, G. Chakraborty, C. H. Wang, R. Rockne, H. L.P. Harpold, M. Muzi, T. C.H. Adamsen, K. A. Krohn, and A. M. Spence Complementary but Distinct Roles for MRI and 18F-Fluoromisonidazole PET in the Assessment of Human Glioblastomas J. Nucl. Med., January 1, 2009; 50(1): 36 - 44. [Abstract] [Full Text] [PDF] |
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A Martelli, N Bernabo, P Berardinelli, V Russo, C Rinaldi, O Di Giacinto, A Mauro, and B Barboni Vascular supply as a discriminating factor for pig preantral follicle selection Reproduction, January 1, 2009; 137(1): 45 - 58. [Abstract] [Full Text] [PDF] |
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H. Udo, Y. Yoshida, T. Kino, K. Ohnuki, W. Mizunoya, T. Mukuda, and H. Sugiyama Enhanced Adult Neurogenesis and Angiogenesis and Altered Affective Behaviors in Mice Overexpressing Vascular Endothelial Growth Factor 120 J. Neurosci., December 31, 2008; 28(53): 14522 - 14536. [Abstract] [Full Text] [PDF] |
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D. G. Nowak, J. Woolard, E. M. Amin, O. Konopatskaya, M. A. Saleem, A. J. Churchill, M. R. Ladomery, S. J. Harper, and D. O. Bates Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors J. Cell Sci., October 15, 2008; 121(20): 3487 - 3495. [Abstract] [Full Text] [PDF] |
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A. Varshavsky, O. Kessler, S. Abramovitch, B. Kigel, S. Zaffryar, G. Akiri, and G. Neufeld Semaphorin-3B Is an Angiogenesis Inhibitor That Is Inactivated by Furin-Like Pro-Protein Convertases Cancer Res., September 1, 2008; 68(17): 6922 - 6931. [Abstract] [Full Text] [PDF] |
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J. Janer, S. Andersson, C. Haglund, R. Karikoski, and P. Lassus Placental Growth Factor and Vascular Endothelial Growth Factor Receptor-2 in Human Lung Development Pediatrics, August 1, 2008; 122(2): 340 - 346. [Abstract] [Full Text] [PDF] |
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G. H. Kim, D. K. Hahn, C. P. Kellner, Z. L. Hickman, R. J. Komotar, R. M. Starke, W. J. Mack, J. Mocco, R. A. Solomon, and E. S. Connolly Jr Plasma Levels of Vascular Endothelial Growth Factor After Treatment for Cerebral Arteriovenous Malformations Stroke, August 1, 2008; 39(8): 2274 - 2279. [Abstract] [Full Text] [PDF] |
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J. A. Ardura, R. Berruguete, D. Ramila, M. V. Alvarez-Arroyo, and P. Esbrit Parathyroid hormone-related protein interacts with vascular endothelial growth factor to promote fibrogenesis in the obstructed mouse kidney Am J Physiol Renal Physiol, August 1, 2008; 295(2): F415 - F425. [Abstract] [Full Text] [PDF] |
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H. Bengoetxea, E. G. Argandona, and J. V. Lafuente Effects of Visual Experience on Vascular Endothelial Growth Factor Expression during the Postnatal Development of the Rat Visual Cortex Cereb Cortex, July 1, 2008; 18(7): 1630 - 1639. [Abstract] [Full Text] [PDF] |
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K. A. Radek, E. J. Kovacs, R. L. Gallo, and L. A. DiPietro Acute ethanol exposure disrupts VEGF receptor cell signaling in endothelial cells Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H174 - H184. [Abstract] [Full Text] [PDF] |
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C. Guruvayoorappan and G. Kuttan (+)-Catechin inhibits tumour angiogenesis and regulates the production of nitric oxide and TNF-{alpha} in LPS-stimulated macrophages Innate Immunity, June 1, 2008; 14(3): 160 - 174. [Abstract] [PDF] |
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S. B. Marko and D. H. Damon VEGF promotes vascular sympathetic innervation Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2646 - H2652. [Abstract] [Full Text] [PDF] |
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I. Barkefors, S. Le Jan, L. Jakobsson, E. Hejll, G. Carlson, H. Johansson, J. Jarvius, J. W. Park, N. Li Jeon, and J. Kreuger Endothelial Cell Migration in Stable Gradients of Vascular Endothelial Growth Factor A and Fibroblast Growth Factor 2: EFFECTS ON CHEMOTAXIS AND CHEMOKINESIS J. Biol. Chem., May 16, 2008; 283(20): 13905 - 13912. [Abstract] [Full Text] [PDF] |
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Z.-L. Wang, X.-P. Xu, B.-L. He, S.-P. Weng, J. Xiao, L. Wang, T. Lin, X. Liu, Q. Wang, X.-Q. Yu, et al. Infectious Spleen and Kidney Necrosis Virus ORF48R Functions as a New Viral Vascular Endothelial Growth Factor J. Virol., May 1, 2008; 82(9): 4371 - 4383. [Abstract] [Full Text] [PDF] |
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S. Banerjee, S. Pancholi, R. A'Hern, Z. Ghazoui, I. E. Smith, M. Dowsett, and L.-A. Martin The Effects of Neoadjuvant Anastrozole and Tamoxifen on Circulating Vascular Endothelial Growth Factor and Soluble Vascular Endothelial Growth Factor Receptor 1 in Breast Cancer Clin. Cancer Res., May 1, 2008; 14(9): 2656 - 2663. [Abstract] [Full Text] [PDF] |
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W. Yan, B. Bentley, and R. Shao Distinct Angiogenic Mediators Are Required for Basic Fibroblast Growth Factor- and Vascular Endothelial Growth Factor-induced Angiogenesis: The Role of Cytoplasmic Tyrosine Kinase c-Abl in Tumor Angiogenesis Mol. Biol. Cell, May 1, 2008; 19(5): 2278 - 2288. [Abstract] [Full Text] [PDF] |
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C Pieh, H Agostini, C Buschbeck, M Kruger, J Schulte-Monting, U Zirrgiebel, J Drevs, and W A Lagreze VEGF-A, VEGFR-1, VEGFR-2 and Tie2 levels in plasma of premature infants: relationship to retinopathy of prematurity Br. J. Ophthalmol., May 1, 2008; 92(5): 689 - 693. [Abstract] [Full Text] [PDF] |
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J. Kim, J. Park, S. Choi, S.-G. Chi, A. L. Mowbray, H. Jo, and H. Park X-Linked Inhibitor of Apoptosis Protein Is an Important Regulator of Vascular Endothelial Growth Factor-Dependent Bovine Aortic Endothelial Cell Survival Circ. Res., April 25, 2008; 102(8): 896 - 904. [Abstract] [Full Text] [PDF] |
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S. R. Soares, R. Gomez, C. Simon, J. A. Garcia-Velasco, and A. Pellicer Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome Hum. Reprod. Update, April 2, 2008; (2008) dmn008v1. [Abstract] [Full Text] [PDF] |
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D. P. Basile, K. Fredrich, B. Chelladurai, E. C. Leonard, and A. R. Parrish Renal ischemia reperfusion inhibits VEGF expression and induces ADAMTS-1, a novel VEGF inhibitor Am J Physiol Renal Physiol, April 1, 2008; 294(4): F928 - F936. [Abstract] [Full Text] [PDF] |
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L. Moreno-Vinasco, M. Gomberg-Maitland, M. L. Maitland, A. A. Desai, P. A. Singleton, S. Sammani, L. Sam, Y. Liu, A. N. Husain, R. M. Lang, et al. Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension Physiol Genomics, April 1, 2008; 33(2): 278 - 291. [Abstract] [Full Text] [PDF] |
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R. Sivakumar, N. Sharma-Walia, H. Raghu, M. V. Veettil, S. Sadagopan, V. Bottero, L. Varga, R. Levine, and B. Chandran Kaposi's Sarcoma-Associated Herpesvirus Induces Sustained Levels of Vascular Endothelial Growth Factors A and C Early during In Vitro Infection of Human Microvascular Dermal Endothelial Cells: Biological Implications J. Virol., February 15, 2008; 82(4): 1759 - 1776. [Abstract] [Full Text] [PDF] |
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C. Salvador, B. Li, R. Hansen, D. E. Cramer, M. Kong, and J. Yan Yeast-Derived {beta}-Glucan Augments the Therapeutic Efficacy Mediated by Anti-Vascular Endothelial Growth Factor Monoclonal Antibody in Human Carcinoma Xenograft Models Clin. Cancer Res., February 15, 2008; 14(4): 1239 - 1247. [Abstract] [Full Text] [PDF] |
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C. M. Becker, N. Rohwer, T. Funakoshi, T. Cramer, W. Bernhardt, A. Birsner, J. Folkman, and R. J. D'Amato 2-Methoxyestradiol Inhibits Hypoxia-Inducible Factor-1{alpha} and Suppresses Growth of Lesions in a Mouse Model of Endometriosis Am. J. Pathol., February 1, 2008; 172(2): 534 - 544. [Abstract] [Full Text] [PDF] |
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M. J. Gray, G. Van Buren, N. A. Dallas, L. Xia, X. Wang, A. D. Yang, R. J. Somcio, Y. G. Lin, S. Lim, F. Fan, et al. Therapeutic Targeting of Neuropilin-2 on Colorectal Carcinoma Cells Implanted in the Murine Liver J Natl Cancer Inst, January 16, 2008; 100(2): 109 - 120. [Abstract] [Full Text] [PDF] |
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S. Choi and J.N. Myers Molecular Pathogenesis of Oral Squamous Cell Carcinoma: Implications for Therapy Journal of Dental Research, January 1, 2008; 87(1): 14 - 32. [Abstract] [Full Text] [PDF] |
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M.-A. Herve, H. Buteau-Lozano, R. Vassy, I. Bieche, G. Velasco, M. Pla, G. Perret, S. Mourah, and M. Perrot-Applanat Overexpression of Vascular Endothelial Growth Factor 189 in Breast Cancer Cells Leads to Delayed Tumor Uptake with Dilated Intratumoral Vessels Am. J. Pathol., January 1, 2008; 172(1): 167 - 178. [Abstract] [Full Text] [PDF] |
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P. Thejass and G. Kuttan Inhibition of Endothelial Cell Differentiation and Proinflammatory Cytokine Production During Angiogenesis by Allyl Isothiocyanate and Phenyl Isothiocyanate Integr Cancer Ther, December 1, 2007; 6(4): 389 - 399. [Abstract] [PDF] |
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J. Lefevre, S.-E. Michaud, P. Haddad, S. Dussault, C. Menard, J. Groleau, J. Turgeon, and A. Rivard Moderate consumption of red wine (cabernet sauvignon) improves ischemia-induced neovascularization in ApoE-deficient mice: effect on endothelial progenitor cells and nitric oxide FASEB J, December 1, 2007; 21(14): 3845 - 3852. [Abstract] [Full Text] [PDF] |
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N. Bahary, K. Goishi, C. Stuckenholz, G. Weber, J. LeBlanc, C. A. Schafer, S. S. Berman, M. Klagsbrun, and L. I. Zon Duplicate VegfA genes and orthologues of the KDR receptor tyrosine kinase family mediate vascular development in the zebrafish Blood, November 15, 2007; 110(10): 3627 - 3636. [Abstract] [Full Text] [PDF] |
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N. C. Rath, W. E. Huff, and G. R. Huff Thiram-Induced Changes in the Expression of Genes Relating to Vascularization and Tibial Dyschondroplasia Poult. Sci., November 1, 2007; 86(11): 2390 - 2395. [Abstract] [Full Text] [PDF] |
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H.-F. Duan, X.-W. Hu, J.-L. Chen, L.-H. Gao, Y.-Y. Xi, Y. Lu, J.-F. Li, S.-R. Zhao, J.-J. Xu, H.-P. Chen, et al. Antitumor Activities of TEM8-Fc: An Engineered Antibody-like Molecule Targeting Tumor Endothelial Marker 8 J Natl Cancer Inst, October 17, 2007; 99(20): 1551 - 1555. [Abstract] [Full Text] [PDF] |
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J. Dai and A.B.M. Rabie VEGF: an Essential Mediator of Both Angiogenesis and Endochondral Ossification Journal of Dental Research, October 1, 2007; 86(10): 937 - 950. [Abstract] [Full Text] [PDF] |
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P. Brownbill, G. C. McKeeman, J. C. Brockelsby, I. P. Crocker, and C. P. Sibley Vasoactive and Permeability Effects of Vascular Endothelial Growth Factor-165 in the Term in Vitro Dually Perfused Human Placental Lobule Endocrinology, October 1, 2007; 148(10): 4734 - 4744. [Abstract] [Full Text] [PDF] |
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D. Krilleke, A. DeErkenez, W. Schubert, I. Giri, G. S. Robinson, Y.-S. Ng, and D. T. Shima Molecular Mapping and Functional Characterization of the VEGF164 Heparin-binding Domain J. Biol. Chem., September 21, 2007; 282(38): 28045 - 28056. [Abstract] [Full Text] [PDF] |
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T. Gustafsson, H. Rundqvist, J. Norrbom, E. Rullman, E. Jansson, and C. J. Sundberg The influence of physical training on the angiopoietin and VEGF-A systems in human skeletal muscle J Appl Physiol, September 1, 2007; 103(3): 1012 - 1020. [Abstract] [Full Text] [PDF] |
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J.-S. Choi, H.-Y. Kim, J.-H. Cha, J.-Y. Choi, S. I. Park, C. H. Jeong, S.-S. Jeun, and M.-Y. Lee Upregulation of Vascular Endothelial Growth Factor Receptors Flt-1 and Flk-1 Following Acute Spinal Cord Contusion in Rats J. Histochem. Cytochem., August 1, 2007; 55(8): 821 - 830. [Abstract] [Full Text] [PDF] |
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J. D. Nagy, E. M. Victor, and J. H. Cropper Why don't all whales have cancer? A novel hypothesis resolving Peto's paradox Integr. Comp. Biol., August 1, 2007; 47(2): 317 - 328. [Abstract] [Full Text] [PDF] |
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E. Zygalaki, E. G. Tsaroucha, L. Kaklamanis, and E. S. Lianidou Quantitative Real-Time Reverse Transcription PCR Study of the Expression of Vascular Endothelial Growth Factor (VEGF) Splice Variants and VEGF Receptors (VEGFR-1 and VEGFR-2) in Non Small Cell Lung Cancer Clin. Chem., August 1, 2007; 53(8): 1433 - 1439. [Abstract] [Full Text] [PDF] |
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A. Szabo, J. Laki, H. O. Madsen, E. Dosa, Z. Prohaszka, S. Rugonfalvi-Kiss, M. Kokai, G. Acsadi, I. Karadi, L. Entz, et al. Early Rise in Serum VEGF and PDGF Levels Predisposes Patients With a Normal MBL2 Genotype to Restenosis After Eversion Endarterectomy Stroke, August 1, 2007; 38(8): 2247 - 2253. [Abstract] [Full Text] [PDF] |
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C. Cappuzzello, R. Melchionna, A. Mangoni, G. Tripodi, P. Ferrari, L. Torielli, D. Arcelli, M. Helmer-Citterich, G. Bianchi, M. C. Capogrossi, et al. Role of rat {alpha} adducin in angiogenesis: Null effect of the F316Y polymorphism Cardiovasc Res, August 1, 2007; 75(3): 608 - 617. [Abstract] [Full Text] [PDF] |
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Y. Wang, J. Chang, K.-D. Chen, S. Li, J. Y.-S. Li, C. Wu, and S. Chien Selective adapter recruitment and differential signaling networks by VEGF vs. shear stress PNAS, May 22, 2007; 104(21): 8875 - 8879. [Abstract] [Full Text] [PDF] |
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S. G. Ball, C. A. Shuttleworth, and C. M. Kielty Vascular endothelial growth factor can signal through platelet-derived growth factor receptors J. Cell Biol., May 7, 2007; 177(3): 489 - 500. [Abstract] [Full Text] [PDF] |
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P. D. Jani, N. Singh, C. Jenkins, S. Raghava, Y. Mo, S. Amin, U. B. Kompella, and B. K. Ambati Nanoparticles Sustain Expression of Flt Intraceptors in the Cornea and Inhibit Injury-Induced Corneal Angiogenesis Invest. Ophthalmol. Vis. Sci., May 1, 2007; 48(5): 2030 - 2036. [Abstract] [Full Text] [PDF] |
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V L Bosquiazzo, J G Ramos, J Varayoud, M Munoz-de-Toro, and E H Luque Mast cell degranulation in rat uterine cervix during pregnancy correlates with expression of vascular endothelial growth factor mRNA and angiogenesis Reproduction, May 1, 2007; 133(5): 1045 - 1055. [Abstract] [Full Text] [PDF] |
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A. B. Dixon, M. Knights, J. L. Winkler, D. J. Marsh, J. L. Pate, M. E. Wilson, R. A. Dailey, G. Seidel, and E. K. Inskeep Patterns of late embryonic and fetal mortality and association with several factors in sheep J Anim Sci, May 1, 2007; 85(5): 1274 - 1284. [Abstract] [Full Text] [PDF] |
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D. Kong, Y. Li, Z. Wang, S. Banerjee, and F. H. Sarkar Inhibition of Angiogenesis and Invasion by 3,3'-Diindolylmethane Is Mediated by the Nuclear Factor-{kappa}B Downstream Target Genes MMP-9 and uPA that Regulated Bioavailability of Vascular Endothelial Growth Factor in Prostate Cancer Cancer Res., April 1, 2007; 67(7): 3310 - 3319. [Abstract] [Full Text] [PDF] |
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S. Jesmin, S. Zaedi, N. Shimojo, M. Iemitsu, K. Masuzawa, N. Yamaguchi, C. N. Mowa, S. Maeda, Y. Hattori, and T. Miyauchi Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1030 - E1040. [Abstract] [Full Text] [PDF] |
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S. H. L. George, M. Gertsenstein, K. Vintersten, E. Korets-Smith, J. Murphy, M. E. Stevens, J. J. Haigh, and A. Nagy Developmental and adult phenotyping directly from mutant embryonic stem cells PNAS, March 13, 2007; 104(11): 4455 - 4460. [Abstract] [Full Text] [PDF] |
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Y. Zhou, Y. Jiang, and Y. J. Kang A BRIEF COMMUNICATION: Copper Inhibition of Hydrogen Peroxide-Induced Hypertrophy in Embryonic Rat Cardiac H9c2 Cells Experimental Biology and Medicine, March 1, 2007; 232(3): 385 - 389. [Abstract] [Full Text] [PDF] |
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N. Shraga-Heled, O. Kessler, C. Prahst, J. Kroll, H. Augustin, and G. Neufeld Neuropilin-1 and neuropilin-2 enhance VEGF121 stimulated signal transduction by the VEGFR-2 receptor FASEB J, March 1, 2007; 21(3): 915 - 926. [Abstract] [Full Text] [PDF] |
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O. Caspi, A. Lesman, Y. Basevitch, A. Gepstein, G. Arbel, I. H. M. Habib, L. Gepstein, and S. Levenberg Tissue Engineering of Vascularized Cardiac Muscle From Human Embryonic Stem Cells Circ. Res., February 2, 2007; 100(2): 263 - 272. [Abstract] [Full Text] [PDF] |
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A. Avivi, L. Brodsky, E. Nevo, and M. R. Band Differential expression profiling of the blind subterranean mole rat Spalax ehrenbergi superspecies: bioprospecting for hypoxia tolerance Physiol Genomics, January 12, 2007; 27(1): 54 - 64. [Abstract] [Full Text] [PDF] |
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L. Piqueras, A. R. Reynolds, K. M. Hodivala-Dilke, A. Alfranca, J. M. Redondo, T. Hatae, T. Tanabe, T. D. Warner, and D. Bishop-Bailey Activation of PPAR{beta}/{delta} Induces Endothelial Cell Proliferation and Angiogenesis Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 63 - 69. [Abstract] [Full Text] [PDF] |
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T.-H. Lee, S. Seng, H. Li, S. J. Kennel, H. K. Avraham, and S. Avraham Integrin Regulation by Vascular Endothelial Growth Factor in Human Brain Microvascular Endothelial Cells: ROLE OF {alpha}6beta1 INTEGRIN IN ANGIOGENESIS J. Biol. Chem., December 29, 2006; 281(52): 40450 - 40460. [Abstract] [Full Text] [PDF] |
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T. Nomura, W.-C. Huang, H. E. Zhau, D. Wu, Z. Xie, H. Mimata, M. Zayzafoon, A. N. Young, F. F. Marshall, M. N. Weitzmann, et al. {beta}2-Microglobulin Promotes the Growth of Human Renal Cell Carcinoma through the Activation of the Protein Kinase A, Cyclic AMP-Responsive Element-Binding Protein, and Vascular Endothelial Growth Factor Axis Clin. Cancer Res., December 15, 2006; 12(24): 7294 - 7305. [Abstract] [Full Text] [PDF] |
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W. Zhang, R. Swanson, Y. Xiong, B. Richard, and S. T. Olson Antiangiogenic Antithrombin Blocks the Heparan Sulfate-dependent Binding of Proangiogenic Growth Factors to Their Endothelial Cell Receptors: EVIDENCE FOR DIFFERENTIAL BINDING OF ANTIANGIOGENIC AND ANTICOAGULANT FORMS OF ANTITHROMBIN TO PROANGIOGENIC HEPARAN SULFATE DOMAINS J. Biol. Chem., December 8, 2006; 281(49): 37302 - 37310. [Abstract] [Full Text] [PDF] |
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A. de Paulis, N. Prevete, I. Fiorentino, F. W. Rossi, S. Staibano, N. Montuori, P. Ragno, A. Longobardi, B. Liccardo, A. Genovese, et al. Expression and Functions of the Vascular Endothelial Growth Factors and Their Receptors in Human Basophils J. Immunol., November 15, 2006; 177(10): 7322 - 7331. [Abstract] [Full Text] [PDF] |
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N. Singh, P. D. Jani, T. Suthar, S. Amin, and B. K. Ambati Flt-1 Intraceptor Induces the Unfolded Protein Response, Apoptotic Factors, and Regression of Murine Injury-Induced Corneal Neovascularization Invest. Ophthalmol. Vis. Sci., November 1, 2006; 47(11): 4787 - 4793. [Abstract] [Full Text] [PDF] |
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M. J. Bizzarro, N. Hussain, B. Jonsson, R. Feng, L. R. Ment, J. R. Gruen, H. Zhang, and V. Bhandari Genetic Susceptibility to Retinopathy of Prematurity Pediatrics, November 1, 2006; 118(5): 1858 - 1863. [Abstract] [Full Text] [PDF] |
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Q. Ke and M. Costa Hypoxia-Inducible Factor-1 (HIF-1) Mol. Pharmacol., November 1, 2006; 70(5): 1469 - 1480. [Abstract] [Full Text] [PDF] |
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H. Xu, L. Zeng, H. Peng, S. Chen, J. Jones, T.-L. Chew, M. M. Sadeghi, Y. S. Kanwar, and F. R. Danesh HMG-CoA reductase inhibitor simvastatin mitigates VEGF-induced "inside-out" signaling to extracellular matrix by preventing RhoA activation Am J Physiol Renal Physiol, November 1, 2006; 291(5): F995 - F1004. [Abstract] [Full Text] [PDF] |
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L. Poliseno, A. Tuccoli, L. Mariani, M. Evangelista, L. Citti, K. Woods, A. Mercatanti, S. Hammond, and G. Rainaldi MicroRNAs modulate the angiogenic properties of HUVECs Blood, November 1, 2006; 108(9): 3068 - 3071. [Abstract] [Full Text] [PDF] |
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W.-U. Kim, S. S. Kang, S.-A. Yoo, K.-H. Hong, D.-G. Bae, M.-S. Lee, S. W. Hong, C.-B. Chae, and C.-S. Cho Interaction of Vascular Endothelial Growth Factor 165 with Neuropilin-1 Protects Rheumatoid Synoviocytes from Apoptotic Death by Regulating Bcl-2 Expression and Bax Translocation J. Immunol., October 15, 2006; 177(8): 5727 - 5735. [Abstract] [Full Text] [PDF] |
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H. R. Lijnen, V. Christiaens, I. Scroyen, G. Voros, M. Tjwa, P. Carmeliet, and D. Collen Impaired adipose tissue development in mice with inactivation of placental growth factor function. Diabetes, October 1, 2006; 55(10): 2698 - 2704. [Abstract] [Full Text] [PDF] |
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S M Hyder Sex-steroid regulation of vascular endothelial growth factor in breast cancer. Endocr. Relat. Cancer, September 1, 2006; 13(3): 667 - 687. [Abstract] [Full Text] [PDF] |
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M. Iemitsu, S. Maeda, S. Jesmin, T. Otsuki, and T. Miyauchi Exercise training improves aging-induced downregulation of VEGF angiogenic signaling cascade in hearts Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1290 - H1298. [Abstract] [Full Text] [PDF] |
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A. D.-Y. Lin, A. Mannikarottu, B. A Kogan, C. Whitbeck, P. Chichester, R. E Leggett, and R. M Levin Estrogen induces angiogenesis of the female rabbit bladder. J. Endocrinol., August 1, 2006; 190(2): 241 - 246. [Abstract] [Full Text] [PDF] |
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J. Tang, Q. Xie, G. Pan, J. Wang, and M. Wang Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion. Eur. J. Cardiothorac. Surg., August 1, 2006; 30(2): 353 - 361. [Abstract] [Full Text] [PDF] |
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M. Atri New Technologies and Directed Agents for Applications of Cancer Imaging J. Clin. Oncol., July 10, 2006; 24(20): 3299 - 3308. [Abstract] [Full Text] [PDF] |
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Y. Su, Z. Cui, Z. Li, and E. R. Block Calpain-2 regulation of VEGF-mediated angiogenesis FASEB J, July 1, 2006; 20(9): 1443 - 1451. [Abstract] [Full Text] [PDF] |
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Y.-J. Na, S.-H. Yang, D.-W. Baek, D.-H. Lee, K.-H. Kim, Y.-M. Choi, S.-T. Oh, Y.-S. Hong, J.-Y. Kwak, and K.-S. Lee Effects of peritoneal fluid from endometriosis patients on the release of vascular endothelial growth factor by neutrophils and monocytes Hum. Reprod., July 1, 2006; 21(7): 1846 - 1855. [Abstract] [Full Text] [PDF] |
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V. Balasubramaniam, A. M. Maxey, D. B. Morgan, N. E. Markham, and S. H. Abman Inhaled NO restores lung structure in eNOS-deficient mice recovering from neonatal hypoxia Am J Physiol Lung Cell Mol Physiol, July 1, 2006; 291(1): L119 - L127. [Abstract] [Full Text] [PDF] |
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J. R. Basile, R. M. Castilho, V. P. Williams, and J. S. Gutkind Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis PNAS, June 13, 2006; 103(24): 9017 - 9022. [Abstract] [Full Text] [PDF] |
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S. Jesmin, S. Zaedi, N. Yamaguchi, S. Maeda, N. Shimojo, K. Masuzawa, I. Yamaguchi, K. Goto, and T. Miyauchi Differential effects of selective endothelin type a receptor antagonist on the gene expression of vascular endothelial growth factor and its receptors in streptozotocin-induced diabetic heart. Experimental Biology and Medicine, June 1, 2006; 231(6): 902 - 906. [Abstract] [Full Text] [PDF] |
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K. A Vonnahme, D. A Redmer, E. Borowczyk, J. J Bilski, J. S Luther, M. L. Johnson, L. P Reynolds, and A. T Grazul-Bilska Vascular composition, apoptosis, and expression of angiogenic factors in the corpus luteum during prostaglandin F2{alpha}-induced regression in sheep. Reproduction, June 1, 2006; 131(6): 1115 - 1126. [Abstract] [Full Text] [PDF] |
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E. Pau, I. Alonso-Muriel, R. Gomez, E. Novella, A. Ruiz, J. A. Garcia-Velasco, C. Simon, and A. Pellicer Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome Hum. Reprod., June 1, 2006; 21(6): 1453 - 1460. [Abstract] [Full Text] [PDF] |
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R. Schindler and R. Mentlein Flavonoids and Vitamin E Reduce the Release of the Angiogenic Peptide Vascular Endothelial Growth Factor from Human Tumor Cells J. Nutr., June 1, 2006; 136(6): 1477 - 1482. [Abstract] [Full Text] [PDF] |
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V. Balasubramaniam, A. M. Maxey, B. W. Fouty, and S. H. Abman Nitric oxide augments fetal pulmonary artery endothelial cell angiogenesis in vitro Am J Physiol Lung Cell Mol Physiol, June 1, 2006; 290(6): L1111 - L1116. [Abstract] [Full Text] [PDF] |
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W. Li, W. Shen, R. Gill, A. Corbly, B. Jones, R. Belagaje, Y. Zhang, S. Tang, Y. Chen, Y. Zhai, et al. High-Resolution Quantitative Computed Tomography Demonstrating Selective Enhancement of Medium-Size Collaterals by Placental Growth Factor-1 in the Mouse Ischemic Hindlimb Circulation, May 23, 2006; 113(20): 2445 - 2453. [Abstract] [Full Text] [PDF] |
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K. Y. Kim and H. G. Cheon Antiangiogenic Effect of Rosiglitazone Is Mediated via Peroxisome Proliferator-activated Receptor {gamma}-activated Maxi-K Channel Opening in Human Umbilical Vein Endothelial Cells J. Biol. Chem., May 12, 2006; 281(19): 13503 - 13512. [Abstract] [Full Text] [PDF] |
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T. Shibuya, K. Watanabe, H. Yamashita, K. Shimizu, H. Miyashita, M. Abe, T. Moriya, H. Ohta, H. Sonoda, T. Shimosegawa, et al. Isolation and Characterization of Vasohibin-2 as a Homologue of VEGF-Inducible Endothelium-Derived Angiogenesis Inhibitor Vasohibin Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1051 - 1057. [Abstract] [Full Text] [PDF] |
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J. A. Marwick, C. S. Stevenson, J. Giddings, W. MacNee, K. Butler, I. Rahman, and P. A. Kirkham Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L897 - L908. [Abstract] [Full Text] [PDF] |
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