Vascular endothelial growth factors VEGF-B and VEGF-C

Abstract

Vascular endothelial growth factor, which was iden-heart cDNA library, respectively, by using a serendipitously found partial mouse cDNA clone as a probe tified almost 10 years ago, has so far been considered as the only growth factor relatively specific for endothelial (20,24). Independently, another group found the same gene when attempting to identify candidate genes for cells. VEGF is an important regulator of endothelial cell proliferation, migration, and permeability during multiple endocrine neoplasia type 1 (MEN1). The product of this alternatively spliced gene was designated as embryonic vasculogenesis and in physiological and pathological angiogenesis [reviewed in (1 -3)]. The piv-VRF (21).The two currently known isoforms of VEGF-B are otal role of VEGF in embryogenesis is emphasized by the unprecedented result that the inactivation of even a generated by alternative splicing of mRNA from the VEGF-B gene, spanning about 4 kb of DNA. The human single VEGF allele results in embryonic lethality (4,5). VEGF acts through its two known high-affinity recep-and murine VEGF-B genes are composed of 7 exons, and their exon -intron organization resembles that of tors Flt1, vascular endothelial growth factor receptor 1 (VEGFR-1) and KDR/Flk1, or VEGFR-2 (6 -10). A VEGF and PlGF genes (21,24,25). The mature VEGF-B proteins (devoid of signal sequence) have 167 (VEGF-third receptor tyrosine kinase homologous with VEGFR-1 and VEGFR-2, designated Flt4, was cloned B 167 ) and 186 (VEGF-B 186 ) amino acid residues, respectively. VEGF-B 186 is generated by using an alternative as an orphan receptor by two research groups and was shown not to bind VEGF (11 -14). Additional VEGF splice acceptor site in exon 6, resulting in an insertion of 101 bp between nucleotides 410 and 411 in the coding receptors of unknown nature also exist on endothelial and tumor cells (15,16).sequence of VEGF-B167. This insertion introduces a frame shift and a stop codon at the position correspond-The second member of the VEGF family of growth factors, placenta growth factor (PlGF), is 53% identical ing to nucleotides 521 -523 of the coding region of VEGF-B 167 cDNA (Fig. 1). Thus, the two VEGF-B iso-with VEGF within its platelet-derived growth factorlike region and binds only VEGFR-1 (17 -19). Both forms have an identical NH2-terminal domain of 115 aa and different COOH-terminal domains. Although VEGF and PlGF are dimeric glycoproteins related in structure to the platelet-derived growth factors A and the C-terminus of VEGF-B 167 is highly basic, that of VEGF-B 186 is rich in alanine, proline, serine, and threo-B (PDGF-A and PDGF-B). This relation is based on the presence of several conserved amino acid residues nine amino acid residues and has no significant similarity with amino acid sequences of known proteins including 8 equally spaced cysteines. Compared with VEGF, the mitogenic or permeability-enhancing activi- (21,24). Unlike other growth factors of the VEGF-family, both isoforms of human and mouse VEGF-B lack ties of PlGF are weak; however, Pl...

Co-Expression of VEGF-C and Its Receptors, VEGFR-2 and VEGFR-3, in Endothelial Cells of Lymphangioma. Implication in Autocrine or Paracrine Regulation of Lymphangioma

“…Thus far, six members are known, which include PDGF, placenta growth factor (PlGF), VEGF, VEGF-B, VEGF-C, and VEGF-D (Achen et al, 1998;Joukov et al, 1996Joukov et al, , 1997Keck et al, 1989;Maglione et al, 1991;Olofsson et al, 1996;Paavonen et al, 1996;Yamada et al, 1997). PDGF is a major mitogen for connective tissue cells and certain other cell types (Heldin and Westermark, 1999), whereas the other five members specifically regulate the growth of endothelial cells in concert with their cognate receptors.…”

Degradation of PKB/Akt protein by inhibition of the VEGF receptor/mTOR pathway in endothelial cells

“…It is secreted mainly from tumor and stroma cells and exerts its angiogenic activity through receptors that are almost exclusively located on endothelial cells (EC). The corresponding VEGF receptor-2 (flk-1/KDR, kinase insert-domain containing receptor) is pivotal for its proangiogenic response because this receptor tyrosine kinase is strongly autophosphorylated on VEGF stimulation (Joukov et al, 1997) and mediates EC mitogenesis and survival (Kroll and Waltenberger, 1997;Takahashi and Shibuya, 1997;Gerber et al, 1998a, b;Shaheen et al, 1999;Bruns et al, 2000;Chan et al, 2002). The importance of VEGF and KDR for tumor angiogenesis is underlined by the fact that both are expressed in high levels when neovascularization occurs (Brown et al, 1993a, b;Itakura et al, 2000) and their expression is strongly associated with tumor grade and vascularity in human neoplasms (Takahashi et al, 1995(Takahashi et al, , 1996Weidner and Folkman, 1996;Ikeda et al, 1999;Chaudhry et al, 2001;Yao et al, 2001).…”

Vascular endothelial growth factor C and D expression correlates with lymph node metastasis and poor prognosis in patients with resected esophageal cancer

“…Vascular endothelial growth factor C (VEGF-C) was initially identified to be a factor stimulating tyrosine kinase receptor Flt4 (VEGFR-3), which was purified from PC-3 prostatic adenocarcinoma cells [7]. The VEGF-C gene is localized on chromosome 4q34 and has a high degree of homology to VEGF-A [8,9]. The open reading frame of VEGF-C c-DNA encodes a protein of 419 amino acid residues, with a predicted molecular mass of 46.9kDa.…”