Vascular Endothelial Growth Factor, a Potent and Selective Angiogenic Agent

INTRODUCTIONThe vascular system is essential for providing oxygen and nutrients, removing metabolic waste products, and furnishing efficient access of leukocytes to tissues throughout larger animals. Angiogenesis, the sprouting of new capillaries, is required for the development of the vascular system and, consequently, the growth of vertebrates. Angiogenic proteins, including several from the fibroblast growth factor family, were identified and purified in the 1980s. They were, however, found to be mitogenic not only for vascular endothelial cells but also for a wide variety of other types of cells and appeared to promote angiogenesis as part of coordinated tissue growth and repair. In the late 1980s the first selective angiogenic growth factor was purified on the basis of its ability to induce transient vascular leakage (vascular permeability factor) and endothelial cell mitogenesis (vascular endothelial growth factor (VEGF) 1The abbreviations used are: VEGFvascular endothelial growth factorPDGFplatelet derived growth factorPlGFplacenta growth factorKDRkinase inset domain-containing receptorFlkfetal liver kinaseFltfms-like tyrosine kinasesFltsoluble Flt. or vasculotropin). By amino acid and cDNA sequencing, these proteins were subsequently demonstrated to be identical. The identification of VEGF 2For simplicity the VEGF nomenclature is generally used in this review to acknowledge the crucial role of this growth factor as an endothelial cell mitogen. set the stage for a rapid expansion in the understanding of what now appears to be one of the most important mediators of physiologic and pathologic angiogenesis yet discovered. Previous reviews have documented some of the initial characterization of VEGF structure and activities (1Neufeld G. Tessler S. Gitay-Goren H. Cohen T. Levi B.-Z. Prog. Growth Factor Res. 1994; 5: 89-97Abstract Full Text PDF PubMed Scopus (210) Google Scholar, 2Ferrara N. Trends Cardiovasc. Med. 1993; 3: 244-250Crossref PubMed Scopus (169) Google Scholar, 3Folkman J. Shing Y. J. Biol. Chem. 1992; 267: 10931-10934Abstract Full Text PDF PubMed Google Scholar). 3Some primary research articles cited in these reviews are not explicitly referenced within this review. Molecular CharacterizationThe originally characterized form of VEGF is an approximately 34-46-kDa homodimeric glycoprotein. The amino acid sequence is ~20% identical with platelet derived growth factor (PDGF) A and B chains (4Leung D.W. Cachianes G. Kuang W.J. Goeddel D.V. Ferrara N. Science. 1989; 246: 1306-1309Crossref PubMed Scopus (4414) Google Scholar, 5Keck P.J. Hauser S.D. Krivi G. Sanzo K. Warren T. Feder J. Connolly D.T. Science. 1989; 246: 1309-1312Crossref PubMed Scopus (1794) Google Scholar, 6Tischer E. Gospodarowicz D. Mitchell R. Silva M. Schilling J. Lau K. Crisp T. Fiddes J.C. Abraham J.A. Biochem. Biophys. Res. Commun. 1989; 165: 1198-1206Crossref PubMed Scopus (253) Google Scholar, 7Conn G. Bayne M.L. Soderman D.D. Kwok P.W. Sullivan K.A. Palisi T.M. Hope D.A. Thomas K.A. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 2628-2633Crossref PubMed Scopus (346) Google Scholar) including 8 conserved Cys residues previously located within the minimal PDGF receptor-binding domain defined by truncated forms of the v-sis-derived oncogenic protein, a viral version of PDGF. In PDGF-BB homodimers, these cysteine residues participate in 3 disulfide bonds within each subunit and 2 symmetric intersubunit disulfide bonds. The amino acid sequence homology implies that the VEGF secondary and tertiary structures, arrangement of intra- and intersubunit disulfide bonds, and relative subunit orientation are similar to those of PDGF.Soon after the identification of VEGF a DNA sequence encoding a close homologue was reported. Denoted placenta growth factor (PlGF) on the basis of its original source, it shares 53% amino acid sequence identity with VEGF, including the 8 conserved Cys residues in the putative receptor-binding domain(8Maglione D. Guerriero V. Viglietto G. Delli Bovi P. Persico Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google with the identity the PDGF A and B In to homodimers, of VEGF and have identified and purified J. Bayne M.L. G. Kwok P.W. Soderman D.D. Palisi T.M. Sullivan K.A. Thomas K.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) in to the is a endothelial cell in only endothelial cell mitogenic similar cDNA of VEGF and that promote the PDGF A the VEGF and are as including forms the of the as in and acid and a the of a acid version have VEGF is of 8 E. Mitchell R. T. Silva M. Gospodarowicz D. Fiddes J.C. Abraham J.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The form of the is by and of the sequence by the acid form in to to and to on and within of the acid sequence by of to these Ferrara N. Biol. 1993; PubMed Scopus Google Scholar). The D. Guerriero V. Viglietto G. K. S. Persico 1993; Google Scholar) that from the by of an acid sequence in an to the VEGF D. Guerriero V. Viglietto G. K. S. Persico 1993; Google Scholar). sequence also in J. K.A. Ferrara N. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar) and in appears to VEGF and to from of and the of forms of VEGF be from and by and by a that is tissue by K.A. D.W. J. Ferrara N. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar). VEGF, a truncated form similar in to not that this of the sequence by the and VEGF from and are by vascular endothelial cells in and in vascular in M. D. Gospodarowicz D. P. Biochem. Biophys. Res. Commun. 1992; PubMed Scopus Google Scholar) and J.A. H. K. Ferrara N. Science. 1992; PubMed Scopus Google each amino acid residues are of the a and an tyrosine The amino acid of and are identical to each is to the homology the domain and of The and the VEGF and are each of the a and tyrosine a truncated form of the by a acid sequence as an of VEGF mitogenic amino acid sequence are in VEGF and with with VEGF but not J. K.A. Ferrara N. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, G. J. Thomas K.A. Biochem. Biophys. Res. Commun. 1994; PubMed Scopus Google Scholar). VEGF to but not an efficient DNA and endothelial cell J. A. M. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). The of mitogenic J. Bayne M.L. G. Kwok P.W. Soderman D.D. Palisi T.M. Sullivan K.A. Thomas K.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) also implies that its to not a mitogenic The mitogenic of is with is by of the to are vascular endothelial cells are in with the role of this as a of endothelial cell J. M. M.L. PubMed Scopus Google Scholar). In endothelial but in of this by VEGF and the of these cells with each other or the on J. M. M.L. PubMed Scopus Google be to forms encoding the or a that is truncated on the of the domain Thomas K.A. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar) as in its for VEGF and G. J. Thomas K.A. Biochem. Biophys. Res. Commun. 1994; PubMed Scopus Google Scholar). the endothelial cell mitogenesis that are to VEGF it not to by the growth other growth factor tyrosine VEGF of and VEGF for the ability of the truncated to the of not on tyrosine to mitogenesis by a it be to not only with but also with the to truncated tyrosine and VEGF A. 1994; PubMed Scopus Google Scholar). of the relative of and a by endothelial cells to VEGF and growth factor by or of the subunit and by and In several other growth factor within the tyrosine tyrosine residues that for with and M. D. Gospodarowicz D. P. Biochem. Biophys. Res. Commun. 1992; PubMed Scopus Google Scholar) and J.A. H. K. Ferrara N. Science. 1992; PubMed Scopus Google Scholar) amino acid tyrosine residues in the are to or of are within the M. P. Biochem. Biophys. Res. Commun. 1994; PubMed Scopus Google endothelial cell also several proteins including some that and participate in proteins the of the to and an that to and and of In the and a one and that cell to other are D. Warren J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The in and that for the in mitogenic are not yet and of is minimal in but is a with the VEGF and of to the VEGF after of the the of each is on vascular and VEGF is in cells the and VEGF is found in cells the of D. A. G. Gitay-Goren H. E. J. 1993; PubMed Scopus Google Scholar) and to the initial of development and M. Ferrara N. 1993; PubMed Scopus Google in several and cell types in In VEGF is in cells and and J. 1993; PubMed Google Scholar). are found in liver and In VEGF is in cells of the and cells of the D. A. G. Gitay-Goren H. E. J. 1993; PubMed Scopus Google Scholar). is within placenta and by vascular endothelial Hauser S. K. D. A. J. Biochem. 1994; PubMed Scopus Google Scholar). is also in several cell J. Bayne M.L. G. Kwok P.W. Soderman D.D. Palisi T.M. Sullivan K.A. Thomas K.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. Guerriero V. Viglietto G. K. S. Persico 1993; Google Scholar) and in in and D. Guerriero V. Viglietto G. K. S. Persico 1993; Google endothelial cell in of VEGF is by a variety of and growth and including E. T. A. 1994; PubMed Scopus Google growth factor growth growth factor S. G. G. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google growth E. T. A. 1994; PubMed Scopus Google Scholar, S. G. G. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. T. A. Ferrara N. K. J. Biol. Chem. 1994; Full Text PDF PubMed Google and J. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google each induce of VEGF from to in a variety of the of of these are mitogenic for endothelial cells in angiogenic activities of VEGF to growth some mediators have to VEGF VEGF in VEGF and in a cell in a by the acid and by in J.A. Sullivan K.A. Thomas K.A. N. J. 1994; PubMed Scopus Google Scholar). one of the of of a on be its of VEGF in is to induce providing a by tissues is one of the most of VEGF D. A. D. E. 1992; PubMed Scopus Google Scholar) and its J. PubMed Scopus Google Scholar) in and of VEGF appears to be a types of cells have to VEGF by approximately as a of the from to the of of VEGF is in including within of D. A. D. E. 1992; PubMed Scopus Google Scholar). of and VEGF in S. D. A. M. G. E. Cardiovasc. Res. 1994; PubMed Scopus Google Scholar). In to of to for VEGF and are in and and in vascular endothelial cells with DNA of J. PubMed Scopus Google by of VEGF is only of VEGF is by and by J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). of is to by of with in the of a putative oxygen its for and the In the and the in the the or similar proteins of VEGF and In DNA that are with the are located to the of the VEGF J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). In a of sequence to a of the VEGF A. S. T. J. Biol. Res. 1994; Google cells throughout the vascular system to other cell types have to in to VEGF, with the endothelial cell of the other cells are to to VEGF, it the most selective vascular endothelial cell also by vascular endothelial cells including Ferrara N. J. 1994; Google Scholar) and the of G. Ferrara N. S. R. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and Ferrara N. E. J. 1992; PubMed Scopus Google Scholar) that of A of VEGF, but not induce vascular leakage in that is within of VEGF to to a in vascular permeability as is in and J. 1993; PubMed Google Scholar). vascular leakage not in to of VEGF, from N. J. T. A. M. T. J. 1993; PubMed Scopus Google or in tissue as the cell an vascular that is not with J. 1993; PubMed Google Scholar). is an of tissue repair. In VEGF is by after in it is vascular new tissue in S. G. G. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). VEGF induce new and in T. S. S. Ferrara N. J. Full Text Full Text PDF PubMed Scopus Google Scholar) and in to in J. S. P. J. E. M. J. in Scholar). VEGF also the of endothelial of the and T. M. S. S. Ferrara N. J. PubMed Scopus Google of VEGF also to of several The growth of appears to be on of VEGF by cells and VEGF in endothelial VEGF appears to be in of to of D. A. D. E. 1992; PubMed Scopus Google Scholar) with the that angiogenesis be in by of VEGF of the to the and growth of in but not growth of the cells in J. M. N. Ferrara N. 1993; PubMed Scopus Google Scholar). the growth by VEGF appears to be a of of of a of the truncated to the tyrosine the growth of a in A. 1994; PubMed Scopus Google by the previously of with VEGF is a of a of in vascular growth in the to in VEGF for most of the angiogenic in or the in H. Ferrara N. N. J. Med. 1994; PubMed Scopus Google Scholar). VEGF also in several characterized by tissues of VEGF and with the Ferrara N. J. 1994; Google Scholar, G. J. Med. 1994; PubMed Scopus Google Scholar). VEGF, and are also in M. J. Med. 1994; PubMed Scopus Google Scholar) and in a G. K.A. J. Google VEGF found the a of the that with in and J. 1994; PubMed Google Scholar). The VEGF amino acid of viral only and identity with putative and are identical to each of viral was previously in the PDGF system in the by the and of a PDGF B vascular endothelial cell and of VEGF have to the of its physiologic as an angiogenic Molecular characterization of the VEGF system selective and that for or of the and that the of VEGF, and understanding of not only the of this system but also of vascular and repair. INTRODUCTIONThe vascular system is essential for providing oxygen and nutrients, removing metabolic waste products, and furnishing efficient access of leukocytes to tissues throughout larger animals. Angiogenesis, the sprouting of new capillaries, is required for the development of the vascular system and, consequently, the growth of vertebrates. Angiogenic proteins, including several from the fibroblast growth factor family, were identified and purified in the 1980s. They were, however, found to be mitogenic not only for vascular endothelial cells but also for a wide variety of other types of cells and appeared to promote angiogenesis as part of coordinated tissue growth and repair. In the late 1980s the first selective angiogenic growth factor was purified on the basis of its ability to induce transient vascular leakage (vascular permeability factor) and endothelial cell mitogenesis (vascular endothelial growth factor (VEGF) 1The abbreviations used are: VEGFvascular endothelial growth factorPDGFplatelet derived growth factorPlGFplacenta growth factorKDRkinase inset domain-containing receptorFlkfetal liver kinaseFltfms-like tyrosine kinasesFltsoluble Flt. or vasculotropin). By amino acid and cDNA sequencing, these proteins were subsequently demonstrated to be identical. The identification of VEGF 2For simplicity the VEGF nomenclature is generally used in this review to acknowledge the crucial role of this growth factor as an endothelial cell mitogen. set the stage for a rapid expansion in the understanding of what now appears to be one of the most important mediators of physiologic and pathologic angiogenesis yet discovered. Previous reviews have documented some of the initial characterization of VEGF structure and activities (1Neufeld G. Tessler S. Gitay-Goren H. Cohen T. Levi B.-Z. Prog. Growth Factor Res. 1994; 5: 89-97Abstract Full Text PDF PubMed Scopus (210) Google Scholar, 2Ferrara N. Trends Cardiovasc. Med. 1993; 3: 244-250Crossref PubMed Scopus (169) Google Scholar, 3Folkman J. Shing Y. J. Biol. Chem. 1992; 267: 10931-10934Abstract Full Text PDF PubMed Google Scholar). 3Some primary research articles cited in these reviews are not explicitly referenced within this review. Molecular CharacterizationThe originally characterized form of VEGF is an approximately 34-46-kDa homodimeric glycoprotein. The amino acid sequence is ~20% identical with platelet derived growth factor (PDGF) A and B chains (4Leung D.W. Cachianes G. Kuang W.J. Goeddel D.V. Ferrara N. Science. 1989; 246: 1306-1309Crossref PubMed Scopus (4414) Google Scholar, 5Keck P.J. Hauser S.D. Krivi G. Sanzo K. Warren T. Feder J. Connolly D.T. Science. 1989; 246: 1309-1312Crossref PubMed Scopus (1794) Google Scholar, 6Tischer E. Gospodarowicz D. Mitchell R. Silva M. Schilling J. Lau K. Crisp T. Fiddes J.C. Abraham J.A. Biochem. Biophys. Res. Commun. 1989; 165: 1198-1206Crossref PubMed Scopus (253) Google Scholar, 7Conn G. Bayne M.L. Soderman D.D. Kwok P.W. Sullivan K.A. Palisi T.M. Hope D.A. Thomas K.A. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 2628-2633Crossref PubMed Scopus (346) Google Scholar) including 8 conserved Cys residues previously located within the minimal PDGF receptor-binding domain defined by truncated forms of the v-sis-derived oncogenic protein, a viral version of PDGF. In PDGF-BB homodimers, these cysteine residues participate in 3 disulfide bonds within each subunit and 2 symmetric intersubunit disulfide bonds. The amino acid sequence homology implies that the VEGF secondary and tertiary structures, arrangement of intra- and intersubunit disulfide bonds, and relative subunit orientation are similar to those of PDGF.Soon after the identification of VEGF a DNA sequence encoding a close homologue was reported. Denoted placenta growth factor (PlGF) on the basis of its original source, it shares 53% amino acid sequence identity with VEGF, including the 8 conserved Cys residues in the putative receptor-binding domain(8Maglione D. Guerriero V. Viglietto G. Delli Bovi P. Persico Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google with the identity the PDGF A and B In to homodimers, of VEGF and have identified and purified J. Bayne M.L. G. Kwok P.W. Soderman D.D. Palisi T.M. Sullivan K.A. Thomas K.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) in to the is a endothelial cell in only endothelial cell mitogenic similar cDNA of VEGF and that promote the PDGF A the VEGF and are as including forms the of the as in and acid and a the of a acid version have VEGF is of 8 E. Mitchell R. T. Silva M. Gospodarowicz D. Fiddes J.C. Abraham J.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The form of the is by and of the sequence by the acid form in to to and to on and within of the acid sequence by of to these Ferrara N. Biol. 1993; PubMed Scopus Google Scholar). The D. Guerriero V. Viglietto G. K. S. Persico 1993; Google Scholar) that from the by of an acid sequence in an to the VEGF D. Guerriero V. Viglietto G. K. S. Persico 1993; Google Scholar). sequence also in J. K.A. Ferrara N. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar) and in appears to VEGF and to from of and the of forms of VEGF be from and by and by a that is tissue by K.A. D.W. J. Ferrara N. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar). VEGF, a truncated form similar in to not that this of the sequence by the and VEGF from and are by vascular endothelial cells in and in vascular in M. D. Gospodarowicz D. P. Biochem. Biophys. Res. Commun. 1992; PubMed Scopus Google Scholar) and J.A. H. K. Ferrara N. Science. 1992; PubMed Scopus Google each amino acid residues are of the a and an tyrosine The amino acid of and are identical to each is to the homology the domain and VEGF and with with VEGF but not J. K.A. Ferrara N. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, G. J. Thomas K.A. Biochem. Biophys. Res. Commun. 1994; PubMed Scopus Google Scholar). VEGF to but not an efficient DNA and endothelial cell J. A. M. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). The of mitogenic J. Bayne M.L. G. Kwok P.W. Soderman D.D. Palisi T.M. Sullivan K.A. Thomas K.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) also implies that its to not a mitogenic The mitogenic of is with is by of the to are vascular endothelial cells are in with the role of this as a of endothelial cell J. M. M.L. PubMed Scopus Google Scholar). In endothelial but in of this by VEGF and the of these cells with each other or the on J. M. M.L. PubMed Scopus Google be to forms encoding the or a that is truncated on the of the domain Thomas K.A. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar) as in its for VEGF and G. J. Thomas K.A. Biochem. Biophys. Res. Commun. 1994; PubMed Scopus Google Scholar). the endothelial cell mitogenesis that are to VEGF it not to by the growth other growth factor tyrosine VEGF of and VEGF for the ability of the truncated to the of not on tyrosine to mitogenesis by a it be to not only with but also with the to truncated tyrosine and VEGF A. 1994; PubMed Scopus Google Scholar). of the relative of and a by endothelial cells to VEGF and growth factor by or of the subunit and by and In several other growth factor within the tyrosine tyrosine residues that for with and M. D. Gospodarowicz D. P. Biochem. Biophys. Res. Commun. 1992; PubMed Scopus Google Scholar) and J.A. H. K. Ferrara N. Science. 1992; PubMed Scopus Google Scholar) amino acid tyrosine residues in the are to or of are within the M. P. Biochem. Biophys. Res. Commun. 1994; PubMed Scopus Google endothelial cell also several proteins including some that and participate in proteins the of the to and an that to and and of In the and a one and that cell to other are D. Warren J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The in and that for the in mitogenic are not yet and of is minimal in but is a with the VEGF and of to the VEGF after of the the of each is on vascular and VEGF is in cells the and VEGF is found in cells the of D. A. G. Gitay-Goren H. E. J. 1993; PubMed Scopus Google Scholar) and to the initial of development and M. Ferrara N. 1993; PubMed Scopus Google in several and cell types in In VEGF is in cells and and J. 1993; PubMed Google Scholar). are found in liver and In VEGF is in cells of the and cells of the D. A. G. Gitay-Goren H. E. J. 1993; PubMed Scopus Google Scholar). is within placenta and by vascular endothelial Hauser S. K. D. A. J. Biochem. 1994; PubMed Scopus Google Scholar). is also in several cell J. Bayne M.L. G. Kwok P.W. Soderman D.D. Palisi T.M. Sullivan K.A. Thomas K.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. Guerriero V. Viglietto G. K. S. Persico 1993; Google Scholar) and in in and D. Guerriero V. Viglietto G. K. S. Persico 1993; Google endothelial cell in of VEGF is by a variety of and growth and including E. T. A. 1994; PubMed Scopus Google growth factor growth growth factor S. G. G. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google growth E. T. A. 1994; PubMed Scopus Google Scholar, S. G. G. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. T. A. Ferrara N. K. J. Biol. Chem. 1994; Full Text PDF PubMed Google and J. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google each induce of VEGF from to in a variety of the of of these are mitogenic for endothelial cells in angiogenic activities of VEGF to growth some mediators have to VEGF VEGF in VEGF and in a cell in a by the acid and by in J.A. Sullivan K.A. Thomas K.A. N. J. 1994; PubMed Scopus Google Scholar). one of the of of a on be its of VEGF in is to induce providing a by tissues is one of the most of VEGF D. A. D. E. 1992; PubMed Scopus Google Scholar) and its J. PubMed Scopus Google Scholar) in and of VEGF appears to be a types of cells have to VEGF by approximately as a of the from to the of of VEGF is in including within of D. A. D. E. 1992; PubMed Scopus Google Scholar). of and VEGF in S. D. A. M. G. E. Cardiovasc. Res. 1994; PubMed Scopus Google Scholar). In to of to for VEGF and are in and and in vascular endothelial cells with DNA of J. PubMed Scopus Google by of VEGF is only of VEGF is by and by J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). of is to by of with in the of a putative oxygen its for and the In the and the in the the or similar proteins of VEGF and In DNA that are with the are located to the of the VEGF J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). In a of sequence to a of the VEGF A. S. T. J. Biol. Res. 1994; Google cells throughout the vascular system to other cell types have to in to VEGF, with the endothelial cell of the other cells are to to VEGF, it the most selective vascular endothelial cell also by vascular endothelial cells including Ferrara N. J. 1994; Google Scholar) and the of G. Ferrara N. S. R. P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and Ferrara N. E. J. 1992; PubMed Scopus Google Scholar) that of A of VEGF, but not induce vascular leakage in that is within of VEGF to to a in vascular permeability as is in and J. 1993; PubMed Google Scholar). vascular leakage not in to of VEGF, from N. J. T. A. M. T. J. 1993; PubMed Scopus Google or in tissue as the cell an vascular that is not with J. 1993; PubMed Google Scholar). is an of tissue repair. In VEGF is by after in it is vascular new tissue in S. G. G. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). VEGF induce new and in T. S. S. Ferrara N. J. Full Text Full Text PDF PubMed Scopus Google Scholar) and in to in J. S. P. J. E. M. J. in Scholar). VEGF also the of endothelial of the and T. M. S. S. Ferrara N. J. PubMed Scopus Google of VEGF also to of several The growth of appears to be on of VEGF by cells and VEGF in endothelial VEGF appears to be in of to of D. A. D. E. 1992; PubMed Scopus Google Scholar) with the that angiogenesis be in by of VEGF of the to the and growth of in but not growth of the cells in J. M. N. Ferrara N. 1993; PubMed Scopus Google Scholar). the growth by VEGF appears to be a of of of a of the truncated to the tyrosine the growth of a in A. 1994; PubMed Scopus Google by the previously of with VEGF is a of a of in vascular growth in the to in VEGF for most of the angiogenic in or the in H. Ferrara N. N. J. Med. 1994; PubMed Scopus Google Scholar). VEGF also in several characterized by tissues of VEGF and with the Ferrara N. J. 1994; Google Scholar, G. J. Med. 1994; PubMed Scopus Google Scholar). VEGF, and are also in M. J. Med. 1994; PubMed Scopus Google Scholar) and in a G. K.A. J. Google VEGF found the a of the that with in and J. 1994; PubMed Google Scholar). The VEGF amino acid of viral only and identity with putative and are identical to each of viral was previously in the PDGF system in the by the and of a PDGF B vascular endothelial cell and of VEGF have to the of its physiologic as an angiogenic Molecular characterization of the VEGF system selective and that for or of the and that the of VEGF, and understanding of not only the of this system but also of vascular and repair.