What Is the Role of Vascular Endothelial Growth Factor-Related Molecules in Tumor Angiogenesis?
1998; Elsevier BV; Volume: 153; Issue: 1 Linguagem: Inglês
10.1016/s0002-9440(10)65539-3
ISSN1525-2191
Autores Tópico(s)Vascular Tumors and Angiosarcomas
ResumoGrowth of solid tumors depends on angiogenesis, the process by which new blood vessels develop from the endothelium of a pre-existing vasculature.1Folkman J What is the evidence that tumors are angiogenesis-dependent?.J Natl Cancer Inst. 1991; 82: 4-6Crossref Scopus (4385) Google Scholar Tumors promote angiogenesis by secreting growth factors that stimulate endothelial migration, proliferation, proteolytic activity, and capillary morphogenesis.2Risau W Angiogenic growth factors.Prog Growth Factor Res. 1990; 2: 71-79Abstract Full Text PDF PubMed Scopus (137) Google Scholar Newly formed blood vessels supply the tumor with nutrients and oxygen, dispose of its metabolic waste products, and generate paracrine stimuli, which further promote tumor cell proliferation and invasiveness.1Folkman J What is the evidence that tumors are angiogenesis-dependent?.J Natl Cancer Inst. 1991; 82: 4-6Crossref Scopus (4385) Google Scholar, 3Nicosia RF Tchao R Leighton J Angiogenesis-dependent tumor spread in reinforced fibrin clot culture.Cancer Res. 1983; 43: 2159-2166PubMed Google Scholar Among the known angiogenic factors, vascular endothelial growth factor (VEGF) has emerged as a central regulator of the angiogenic process in physiological and pathological conditions.4Ferrara N Davis-Smyth T The biology of vascular endothelial growth factor.Endocr Rev. 1997; 18: 4-25Crossref PubMed Scopus (3667) Google Scholar This molecule was first named vascular permeability factor by Dvorak and co-workers because of its potent stimulatory effect on the permeability of the tumor microvasculature.5Senger DR Galli SJ Dvorak AM Peruzzi CA Harvey VS Dvorak HF Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.Science. 1983; 219: 983-985Crossref PubMed Scopus (3388) Google Scholar Ferrara et al6Leung DW Cachianes G Kuang W-J Goeddel DV Ferrara N Vascular endothelial growth factor is a secreted angiogenic mitogen.Science. 1989; 246: 1306-1309Crossref PubMed Scopus (4424) Google Scholar coined the term VEGF to describe a mitogenic factor that selectively stimulated endothelial cell proliferation and angiogenesis. The same molecule was independently discovered by others.7Plouet J Schilling J Gospodarowicz D Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT20 cells.EMBO J. 1989; 8: 3801-3806PubMed Google Scholar, 8Conn G Bayne M Soderman L Kwok PW Sullivan KA Palisi TN Hope DA Thomas KA Amino acid and cDNA sequence of a vascular endothelial cell mitogen homologous to platelet-derived growth factor.Proc Natl Acad Sci USA. 1990; 87: 2628-2632Crossref PubMed Scopus (346) Google Scholar Connolly et al9Connolly DT Heivelman DM Nelson R Olander JV Eppley BL Delfino JJ Siegel NR Leimgruber RM Feder J Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis.J Clin Invest. 1989; 84: 1470-1478Crossref PubMed Scopus (1177) Google Scholar reported that vascular permeability factor was mitogenic for endothelial cells and had the capacity to stimulate vascular proliferation. Sequence analysis of cDNAs demonstrated that vascular permeability factor and VEGF were the same molecule.4Ferrara N Davis-Smyth T The biology of vascular endothelial growth factor.Endocr Rev. 1997; 18: 4-25Crossref PubMed Scopus (3667) Google Scholar Recently, the VEGF family of growth factors has expanded with the addition of four new molecules: placenta growth factor (PlGF), VEGF-B, VEGF-C, and VEGF-D (Table 1).10Maglione D Guerriero V Viglietto G Delli-Bovi P Persico MG Isolation of a human placental cDNA coding for a protein related to the vascular permeability factor.Proc Natl Acad Sci USA. 1991; 88: 9267-9271Crossref PubMed Scopus (831) Google Scholar, 11Olofsson B Pajusola K Kaipanen A von Euler G Joukov V Saksela O Orpana A Petterson RF Alitalo K Eriksson U Vascular endothelial growth factor B, a novel growth factor for endothelial cells.Proc Natl Acad Sci USA. 1996; 93: 2576-2581Crossref PubMed Scopus (620) Google Scholar, 12Kukk E Lymboussaki Taira S Kaipanen A Jeltsch M Joukov V Alitalo K VEGF-C receptor binding, and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development.Development. 1996; 122: 3829-3837PubMed Google Scholar, 13Yamada Y Nezu J Shimane M Hirata Y Molecular cloning of a novel vascular endothelial growth factor, VEGF-D.Genomics. 1997; 42: 483-488Crossref PubMed Scopus (225) Google Scholar VEGF and VEGF-related molecules have homologous amino acid sequences including eight cysteine residues, which are also found in platelet-derived growth factors A and B, and bind to the same class of tyrosine kinase receptors.4Ferrara N Davis-Smyth T The biology of vascular endothelial growth factor.Endocr Rev. 1997; 18: 4-25Crossref PubMed Scopus (3667) Google Scholar, 8Conn G Bayne M Soderman L Kwok PW Sullivan KA Palisi TN Hope DA Thomas KA Amino acid and cDNA sequence of a vascular endothelial cell mitogen homologous to platelet-derived growth factor.Proc Natl Acad Sci USA. 1990; 87: 2628-2632Crossref PubMed Scopus (346) Google Scholar In this issue of theAmerican Journal of Pathology, Salven et al14Salven P Lymboussaki A Heikkilä Jääskelä-Saari Aase K von Euler G Eriksson U Alitalo K Joensuu H Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors.Am J Pathol. 1998; 153: 103-108Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar report that VEGF-B and VEGF-C are expressed in a variety of human tumors. This commentary briefly reviews our knowledge of this field and critically evaluates the potential role of VEGF-related molecules in tumor angiogenesis and neoplastic progression.Table 1VEGF and VEGF-Related MoleculesLigandIsoformsChromosome*Chromosome localization refers to human genes.ReceptorVascular targetVEGFVEGF1216pVEGFR-1Hematic endotheliumVEGF165VEGFR-2VEGF189VEGF206VEGF145PlGFPlGF-114qVEGFR-1Hematic endotheliumPlGF-2PlGF-3VEGF-BVEGF-B16711qVEGFR-1Hematic endotheliumVEGF-B186VEGF-CVEGF-C4qVEGFR-2Lymphatic endotheliumVEGFR-3Hematic endotheliumVEGF-DVEGF-DXpVEGFR-2Lymphatic endotheliumVEGFR-3Hematic endothelium* Chromosome localization refers to human genes. Open table in a new tab VEGF comprises four main isoforms produced by alternative splicing of mRNA: VEGF121, VEGF165, VEGF189, VEGF206.4Ferrara N Davis-Smyth T The biology of vascular endothelial growth factor.Endocr Rev. 1997; 18: 4-25Crossref PubMed Scopus (3667) Google Scholar, 15Wei MH Popescu NC Lerman MI Merrill MJ Zimonjic DB Localization of the human vascular endothelial growth factor gene, VEGF, at chromosome 6p12.Hum Genet. 1996; 97: 794-797Crossref PubMed Scopus (48) Google Scholar A fifth isoform, VEGF145, has been found in placental cells and carcinoma cells from the female reproductive tract.16Poltorak Z Cohen T Silvan R Kandelis Y Spira G Vlodavsky I Keshet E Neufeld G VEGF145, a secreted vascular endothelial growth factor isoform that binds to the extracellular matrix.J Biol Chem. 1992; 272: 7151-7158Google Scholar VEGF molecules have a signal peptide sequence and are secreted as homodimers through conventional pathways.4Ferrara N Davis-Smyth T The biology of vascular endothelial growth factor.Endocr Rev. 1997; 18: 4-25Crossref PubMed Scopus (3667) Google Scholar The mature form of VEGF is the VEGF165 homodimer, which has a molecular weight of∼ 45 kd. VEGF189 and VEGF206 are the most basic isoforms, bind to heparin with greater affinity than VEGF165, and are almost completely sequestered in the extracellular matrix. VEGF121, which is slightly acidic because it lacks the basic amino acids responsible for heparin binding, is the most soluble isoform. In the extracellular compartment, plasmin cleaves a portion of the VEGF molecule, generating a 34-kd protein that consists of the first 110 NH2-terminal amino acids.17Houck KA Leung DW Rowland AM Winer J Ferrara N Dual regulation of vascular endothelial growth factor availability by genetic and proteolytic mechanisms.J Biol Chem. 1992; 267: 26032-26037Google Scholar This may be a mechanism whereby bioactive VEGF is released by proteolysis from larger isoforms sequestered in the extracellular matrix.4Ferrara N Davis-Smyth T The biology of vascular endothelial growth factor.Endocr Rev. 1997; 18: 4-25Crossref PubMed Scopus (3667) Google Scholar, 17Houck KA Leung DW Rowland AM Winer J Ferrara N Dual regulation of vascular endothelial growth factor availability by genetic and proteolytic mechanisms.J Biol Chem. 1992; 267: 26032-26037Google Scholar VEGF binds with high affinity to two tyrosine kinase receptors: VEGF receptor (VEGFR)-1 (Flt-1) and VEGFR-2 (KDR/Flk-1).4Ferrara N Davis-Smyth T The biology of vascular endothelial growth factor.Endocr Rev. 1997; 18: 4-25Crossref PubMed Scopus (3667) Google Scholar, 18Vaisman N Gospodarowicz D Neufeld G Characterization of the receptors for vascular endothelial growth factor.J Biol Chem. 1990; 265: 19461-19469Abstract Full Text PDF PubMed Google Scholar, 19Mustonen T Alitalo K Endothelial receptor tyrosine kinases involved in angiogenesis.J Cell Biol. 1995; 129: 895-898Crossref PubMed Scopus (475) Google Scholar Binding of VEGF causes receptor dimerization followed by autophosphorylation of the receptor and signal transduction. There are significant differences between VEGFR-1 and VEGFR-2. For example, endothelial cells without endogenous VEGFRs migrate and proliferate in response to VEGF when transfected with VEGFR-2 but lack such responses if transfected with VEGFR-1.20Waltenberger J Claesson-Welsh L Siegbahn A Shibuya M Heldin C-H Different signal transduction properties of KDR and Flt-1, two receptors for vascular endothelial growth factor.J Biol Chem. 1994; 269: 26988-26995Abstract Full Text PDF PubMed Google Scholar VEGFR-1 is, however, capable of mediating PIGF-induced endothelial cell proliferation and plasminogen activator expression.61Landgren E Schiller P Cao Y Claesson-Welsh L Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-γ and migration of endothelial cells expressing Flt 1.Oncogene. 1998; 16: 359-367Crossref PubMed Scopus (147) Google Scholar Gene knockout experiments have confirmed a critical role in angiogenesis for both VEGFR-1 and VEGFR-2.21Shalaby F Rossant J Yamaguchi TP Gertenstein M Wu XF Breltman ML Schuh AC Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice.Nature. 1995; 376: 62-66Crossref PubMed Scopus (3338) Google Scholar, 22Fong G-H, Rossant J, Getenstein M, Breitman M: Role of Flt-1 receptor tyrosine kinase in regulation of assembly of vascular endothelium. Nature, 376:66–67Google Scholar Inactivation of the VEGFR-2 gene causes failure of vasculogenesis, the process of de novo formation of blood vessels from undifferentiated mesenchyme.21Shalaby F Rossant J Yamaguchi TP Gertenstein M Wu XF Breltman ML Schuh AC Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice.Nature. 1995; 376: 62-66Crossref PubMed Scopus (3338) Google Scholar VEGFR-2 knockout embryos are unable to form blood islands and to generate hemopoietic precursors. Targeted mutation of the VEGFR-1 gene does not affect the differentiation of endothelial cells but causes a disorganized assembly of the developing vasculature.22Fong G-H, Rossant J, Getenstein M, Breitman M: Role of Flt-1 receptor tyrosine kinase in regulation of assembly of vascular endothelium. Nature, 376:66–67Google Scholar Because of vascular abnormalities, both VEGFR-1 and VEGFR-2 knockout embryos die in utero between days 8.5 and 9.5. Embryos having a single (VEGF+/−) or both VEGF (VEGF −/−) alleles defective suffer from a failure of vasculogenesis, leading to intrauterine death by day 10 to 12.23Ferrara N Carver-Moore K Chen H Dowd M Lu L O'Shea KS Powell-Braxton L Hillan KJ Moore MW Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene.Nature. 1996; 380: 439-442Crossref PubMed Scopus (3026) Google Scholar The demonstration of a vasculogenic defect also in heterozygous embryos (VEGF+/−) suggests that there is a critical threshold of VEGF levels below which new blood vessels are unable to form.23Ferrara N Carver-Moore K Chen H Dowd M Lu L O'Shea KS Powell-Braxton L Hillan KJ Moore MW Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene.Nature. 1996; 380: 439-442Crossref PubMed Scopus (3026) Google Scholar VEGF stimulates the migration and proliferation of arterial, venous, and microvascular endothelial cells as well as angiogenesis in vivo and in vitro.4Ferrara N Davis-Smyth T The biology of vascular endothelial growth factor.Endocr Rev. 1997; 18: 4-25Crossref PubMed Scopus (3667) Google Scholar, 6Leung DW Cachianes G Kuang W-J Goeddel DV Ferrara N Vascular endothelial growth factor is a secreted angiogenic mitogen.Science. 1989; 246: 1306-1309Crossref PubMed Scopus (4424) Google Scholar, 7Plouet J Schilling J Gospodarowicz D Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT20 cells.EMBO J. 1989; 8: 3801-3806PubMed Google Scholar, 9Connolly DT Heivelman DM Nelson R Olander JV Eppley BL Delfino JJ Siegel NR Leimgruber RM Feder J Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis.J Clin Invest. 1989; 84: 1470-1478Crossref PubMed Scopus (1177) Google Scholar VEGF promotes the balanced degradation of the extracellular matrix around the sprouting endothelium by inducing the expression of urokinase-type plasminogen activator, tissue-type plasminogen activator, plasminogen activator inhibitor-1,24Pepper MS Ferrara N Orci L Montesano R Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor type 1 in microvascular endothelial cells.J Cell Physiol. 1992; 181: 902-908Google Scholar and interstitial collagenase.25Unemori EN Ferrara N Bauer EA Amento EP Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells.J Cell Physiol. 1992; 153: 557-562Crossref PubMed Scopus (457) Google Scholar By enhancing the permeability of venules to circulating proteins including fibrinogen, VEGF is believed to facilitate the perivascular deposition of fibrin, which further potentiates angiogenesis.26Dvorak HF Brown LF Detmar M Dvorak AM Vascular permeability factor/vascular endothelial growth factor, microvascular permeability, and angiogenesis.Am J Pathol. 1995; 36: 139-155Google Scholar Through its capacity to induce nitric oxide, VEGF may also mediate the vasodilation and increased blood flow that precede angiogenesis.27Ku DD Jaleski JK Liu S Brock TA Vascular endothelial growth factor induces EDRF-dependent relaxation in coronary arteries.Am J Physiol. 1993; 265: H586-H592PubMed Google Scholar The PlGF gene encodes three alternatively spliced isoforms with different secretion patterns, heparin binding affinities, and dimerization properties: PlGF-1, PlGF-2, and PlGF-3.10Maglione D Guerriero V Viglietto G Delli-Bovi P Persico MG Isolation of a human placental cDNA coding for a protein related to the vascular permeability factor.Proc Natl Acad Sci USA. 1991; 88: 9267-9271Crossref PubMed Scopus (831) Google Scholar, 28Maglione D Guerriero V Viglietto G Ferraro MG Aprelikova O Alitalo K Del Vecchio S Lei KJ Chou JY Persico MG Two alternative mRNAs coding for the angiogenic factor placenta growth factor (Plgf), are transcribed from a single gene of chromosome 14.Oncogene. 1993; 8: 925-931PubMed Google Scholar, 29Hauser S Wech HA A heparin-binding form of placental growth factor (Plgf-2) is expressed in human umbilical vein endothelial cells, and in placenta.Growth Factors. 1993; 9: 259-268Crossref PubMed Scopus (202) Google Scholar, 30Cao Y Weidong-Richard Ji Pang Qi Rosin A Cao Y Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing.Biochem Biophys Res Commun. 1997; 235: 493-498Crossref PubMed Scopus (154) Google Scholar PlGF binds with high affinity to VEGFR-1 but not to VEGFR-2.31Park JE Chen H Winer J Houck K Ferrara N 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; 269: 25646-25654Abstract Full Text PDF PubMed Google Scholar The expression of PlGF is restricted to the placenta and is not observed in the majority of normal adult tissues.30Cao Y Weidong-Richard Ji Pang Qi Rosin A Cao Y Placenta growth factor: identification and characterization of a novel isoform generated by RNA alternative splicing.Biochem Biophys Res Commun. 1997; 235: 493-498Crossref PubMed Scopus (154) Google Scholar Because it forms heterodimers with VEGF, which are less potent than VEGF homodimers, PlGF may reduce the bioavailability of active VEGF molecules.32Cao Y Chn H Zhou L Chiang MK Anand-Apte B Weatherbee JA Wang Y Fang F Flanagan JG Tsang ML Heterodimers of placenta growth factor/vascular endothelial growth factor: endothelial activity, tumor cell expression, and high affinity binding to Flk-1/KDR.J Biol Chem. 1996; 271: 3154-3162Crossref PubMed Scopus (258) Google Scholar PlGF, however, can also potentiate the activity of suboptimal concentrations of VEGF.31Park JE Chen H Winer J Houck K Ferrara N 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; 269: 25646-25654Abstract Full Text PDF PubMed Google Scholar Recently, Ziche et al33Ziche M Maglione D Ribatti D Morbidelli L Lago CT Battisti M Paoletti I Barra A Tucci M Parise G Vincenti V Granger HJ Viglietto G Persico MG Placenta growth factor-1 is chemotactic, mitogenic and angiogenic.Lab Invest. 1997; 76: 517-531PubMed Google Scholar reported that recombinant PlGF-1 purified from overexpressing eukaryotic cells was as effective as VEGF and basic fibroblast growth factor in stimulating angiogenesis in the rabbit cornea assay. They also noticed that the mitogenic effect of PlGF-1 was dependent on the endothelial cell type. On this basis, they suggested that the preferential target of PlGF-1 is the endothelium of postcapillary venules, whereas VEGF stimulates with equal potency both macrovascular and microvascular endothelium. VEGF-B is present in a variety of normal organs and is particularly abundant in heart and skeletal muscle. There are two alternatively spliced isoforms of VEGF-B: VEGF-B167 and VEGF-B186.11Olofsson B Pajusola K Kaipanen A von Euler G Joukov V Saksela O Orpana A Petterson RF Alitalo K Eriksson U Vascular endothelial growth factor B, a novel growth factor for endothelial cells.Proc Natl Acad Sci USA. 1996; 93: 2576-2581Crossref PubMed Scopus (620) Google Scholar, 34Oloffsson B Pajusola K von Euler G Chilov D Alitalo K Eriksson U Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform.J Biol Chem. 1996; 271: 19310-19317Crossref PubMed Scopus (164) Google Scholar, 35Paavonen K Horelli-Kuitunen N Chilov D Kukk E Pennanen S Kallioniemi OP Pajusola K Olofsson B Eriksson U Joukov V Palotie A Alitalo K Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q34 and 4q34, respectively.Circulation. 1996; 93: 1079-1082Crossref PubMed Scopus (83) Google Scholar VEGF-B167 is a highly basic heparin-binding protein which, similarly to VEGF189 and VEGF206, remains associated with the cell or the extracellular matrix and is not released into the culture medium unless cells are treated with heparin. VEGF-B186 homodimers, on the other hand, are readily secreted.34Oloffsson B Pajusola K von Euler G Chilov D Alitalo K Eriksson U Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform.J Biol Chem. 1996; 271: 19310-19317Crossref PubMed Scopus (164) Google Scholar VEGF-B can form disulfide-linked heterodimers with VEGF and influence the bioavailability of this molecule, as described for PlGF.11Olofsson B Pajusola K Kaipanen A von Euler G Joukov V Saksela O Orpana A Petterson RF Alitalo K Eriksson U Vascular endothelial growth factor B, a novel growth factor for endothelial cells.Proc Natl Acad Sci USA. 1996; 93: 2576-2581Crossref PubMed Scopus (620) Google Scholar, 34Oloffsson B Pajusola K von Euler G Chilov D Alitalo K Eriksson U Genomic organization of the mouse and human genes for vascular endothelial growth factor B (VEGF-B) and characterization of a second splice isoform.J Biol Chem. 1996; 271: 19310-19317Crossref PubMed Scopus (164) Google Scholar VEGF-B stimulates endothelial cell proliferation, but it does not bind to VEGFR-2. Recent studies indicate that the function of VEGF-B is mediated by VEGFR-1 (Olefsson, Kerpelainen, Mandriota, Pepper, Aase, Kumar, Ganji, Jelisch, Shibuya, Alitalo, and Eriksson, unpublished manuscript). VEGF-C is produced as a propeptide that is proteolytically cleaved to a 21-kd molecule.12Kukk E Lymboussaki Taira S Kaipanen A Jeltsch M Joukov V Alitalo K VEGF-C receptor binding, and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development.Development. 1996; 122: 3829-3837PubMed Google Scholar, 35Paavonen K Horelli-Kuitunen N Chilov D Kukk E Pennanen S Kallioniemi OP Pajusola K Olofsson B Eriksson U Joukov V Palotie A Alitalo K Novel human vascular endothelial growth factor genes VEGF-B and VEGF-C localize to chromosomes 11q34 and 4q34, respectively.Circulation. 1996; 93: 1079-1082Crossref PubMed Scopus (83) Google Scholar, 36Joukov V Sorsa T Kumar V Jeltsch M Claesson-Welsh L Cao Y Saksela O Kalkkinen N Alitalo K Proteolytic processing regulates receptor specificity and activity of VEGF-C.EMBO J. 1997; 16: 3898-3911Crossref PubMed Scopus (640) Google Scholar Unlike some of the VEGF, VEGF-B, and PlGF isoforms, VEGF-C does not bind to heparin. VEGF-C increases vascular permeability and stimulates the migration and proliferation of endothelial cells, but at a significantly higher concentration than VEGF.12Kukk E Lymboussaki Taira S Kaipanen A Jeltsch M Joukov V Alitalo K VEGF-C receptor binding, and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development.Development. 1996; 122: 3829-3837PubMed Google Scholar VEGF-C binds to and induces autophosphorylation of the tyrosine kinase receptor Flt-4, which has been renamed VEGFR-3.12Kukk E Lymboussaki Taira S Kaipanen A Jeltsch M Joukov V Alitalo K VEGF-C receptor binding, and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development.Development. 1996; 122: 3829-3837PubMed Google Scholar VEGF-C also activates VEGFR-2 but not VEGFR-1.12Kukk E Lymboussaki Taira S Kaipanen A Jeltsch M Joukov V Alitalo K VEGF-C receptor binding, and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development.Development. 1996; 122: 3829-3837PubMed Google Scholar Proteolytic processing of VEGF-C generates several VEGF-C forms with increased activity toward VEGFR-3, but only the fully processed VEGF-C can bind to VEGFR-2.36Joukov V Sorsa T Kumar V Jeltsch M Claesson-Welsh L Cao Y Saksela O Kalkkinen N Alitalo K Proteolytic processing regulates receptor specificity and activity of VEGF-C.EMBO J. 1997; 16: 3898-3911Crossref PubMed Scopus (640) Google Scholar VEGF-C has greater affinity for VEGFR-3 than VEGFR-2. The other members of the VEGF family, with the exception of VEGF-D (see below), are unable to activate VEGFR-3. VEGF-C is expressed during embryonal development in regions where lymphatics sprout from venous vessels.12Kukk E Lymboussaki Taira S Kaipanen A Jeltsch M Joukov V Alitalo K VEGF-C receptor binding, and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development.Development. 1996; 122: 3829-3837PubMed Google Scholar VEGF-C is present also in adult tissues, where it is postulated to play a role in the maintenance of lymphatic endothelial differentiation.12Kukk E Lymboussaki Taira S Kaipanen A Jeltsch M Joukov V Alitalo K VEGF-C receptor binding, and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development.Development. 1996; 122: 3829-3837PubMed Google Scholar VEGFR-3 is highly expressed in angioblasts, veins, and lymphatics during embryonal vasculogenesis but becomes largely restricted to the lymphatic endothelium in adult tissues.12Kukk E Lymboussaki Taira S Kaipanen A Jeltsch M Joukov V Alitalo K VEGF-C receptor binding, and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development.Development. 1996; 122: 3829-3837PubMed Google Scholar, 37Kaipanen A Korhonen J Mutsonen T van Hinsberg Fang GH Dumont D Breitman M Alitalo K Expression of the FLT4 receptor tyrosine kinase becomes restricted to endothelium of lymphatic vessels and some high endothelial venules during development.Proc Natl Acad Sci USA. 1995; 92: 3566-3570Crossref PubMed Scopus (1176) Google Scholar VEGFR-3 is also expressed in the high venular endothelium of lymph nodes.37Kaipanen A Korhonen J Mutsonen T van Hinsberg Fang GH Dumont D Breitman M Alitalo K Expression of the FLT4 receptor tyrosine kinase becomes restricted to endothelium of lymphatic vessels and some high endothelial venules during development.Proc Natl Acad Sci USA. 1995; 92: 3566-3570Crossref PubMed Scopus (1176) Google Scholar Because of their patterns of expression, VEGF-C and VEGFR-3 have been implicated in lymphangiogenesis, the process of formation of new lymphatics. Exogenous VEGF-C selectively stimulates lymphatic proliferation in the chorioallantoic membrane, whereas VEGF promotes angiogenesis from blood vessels.38Oh SJ Jeltsch MM Birkenhäger R McCarthy JEG Weich HA Christ B Alitalo K Wilting J VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane.Dev Biol. 1997; 188: 96-109Crossref PubMed Scopus (432) Google Scholar Consistent with these observations, targeted overexpression of VEGF-C in the skin of transgenic mice causes lymphatic hyperplasia.39Jeltsch MM Kaipanen A Joukov V Meng X Lakso M Rauval H Swartz M Fukumura D Jain RK Alitalo K Hyperplasia of lymphatic vessels in VEGF-C transgenic mice.Science. 1997; 276: 1423-1425Crossref PubMed Scopus (1107) Google Scholar The targeted effect of VEGF-C is probably linked to the formation of VEGFR-2/VEGFR-3 heterodimers in lymphatic endothelial cells.39Jeltsch MM Kaipanen A Joukov V Meng X Lakso M Rauval H Swartz M Fukumura D Jain RK Alitalo K Hyperplasia of lymphatic vessels in VEGF-C transgenic mice.Science. 1997; 276: 1423-1425Crossref PubMed Scopus (1107) Google Scholar VEGF-D, the newest member of the VEGF family, is 48% identical to VEGF-C.13Yamada Y Nezu J Shimane M Hirata Y Molecular cloning of a novel vascular endothelial growth factor, VEGF-D.Genomics. 1997; 42: 483-488Crossref PubMed Scopus (225) Google Scholar Both VEGF-C and VEGF-D have long NH2-and C-terminal extensions, which set these growth factors apart as a subfamily of VEGF-related proteins. VEGF-D is induced byc-fos40Orlandini M Marconcini L Ferruzzi R Oliviero S Identification of a c-fos-induced gene that is related to the platelet-derived growth factor/vascular endothelial growth factor family.Proc Natl Acad Sci USA. 1996; 93: 11675-11680Crossref PubMed Scopus (262) Google Scholar and is strongly expressed in the fetal lung during development. In the adult it is primarily found in skeletal muscle, heart, lung, and intestine.13Yamada Y Nezu J Shimane M Hirata Y Molecular cloning of a novel vascular endothelial growth factor, VEGF-D.Genomics. 1997; 42: 483-488Crossref PubMed Scopus (225) Google Scholar VEGF-D is a ligand for both VEGFR-2 and VEGFR-3, but does not bind to the VEGFR-1.41Achen M Jeltsch M Kukk E Mäkinen T Vitali A Wilks AF Alitalo K Stacker SA Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinase VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4).Proc Natl Acad Sci USA. 1998; 95: 548-553Crossref PubMed Scopus (1013) Google Scholar In addition, VEGF-D stimulates the proliferation of endothelial cells.41Achen M Jeltsch M Kukk E Mäkinen T Vitali A Wilks AF Alitalo K Stacker SA Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinase VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4).Proc Natl Acad Sci USA. 1998; 95: 548-553Crossref PubMed Scopus (1013) Google Scholar Members of the VEGF family are regulated by different mechanisms. For example, serum, growth factors, and inflammatory cytokines increase VEGF and VEGF-C mRNAs but have no effect on VEGF-B.42Enholm B Paavonen K Ristimäki A Kumar V Gunji Y Klefstrom J Kivinen L Laiho M Olofsson B Joukov V Eriksson U Alitalo K Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia.Oncogene. 1997; 14: 2475-2483Crossref PubMed Scopus (385) Google Scholar, 62Ristimaki A Narko K Enholm B Joukov V Alitalo K Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor C. J.Biol Chem. 1998; 273: 8413-8418Crossref Scopus (343) Google Scholar Amplification of the ras oncogene causes up-regulation of VEGF4Ferrara N Davis-Smyth T The biology of vascular endothelial growth factor.Endocr Rev. 1997; 18: 4-25Crossref PubMed Scopus (3667) Google Scholar but leaves unaltered the expression of VEGF-B and VEGF-C.42Enholm B Paavonen K Ristimäki A Kumar V Gunji Y Klefstrom J Kivinen L Laiho M Olofsson B Joukov V Eriksson U Alitalo K Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia.Oncogene. 1997; 14: 2475-2483Crossref PubMed Scopus (385) Google Scholar Hypoxia strongly induces VEGF mRNA expression but has no
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