(Circulation. 1996;93:1079-1082.)
© 1996 American Heart Association, Inc.
Articles |
Novel Human Vascular Endothelial Growth Factor Genes VEGF-B and VEGF-C Localize to Chromosomes 11q13 and 4q34, Respectively
From the Molecular/Cancer Biology Laboratory, Haartman Institute (K. Paavonen, K. Pajusola, D.C., E.K., V.J., K.A.), Helsinki, Finland; the Department of Clinical Chemistry (N.H-K., A.P.), Helsinki University Central Hospital, Helsinki, Finland; the Laboratory of Cancer Genetics (S.P., O.-P.K.), University of Tampere Institute of Medical Technology, Tampere, Finland; and Ludwig Institute for Cancer Research (B.O., U.E.), Stockholm Branch, Stockholm, Sweden.
Correspondence to Kari Alitalo, Molecular/Cancer Biology Laboratory, Haartman Institute, PO Box 21 (Haartmanninkatu 3), 00014 Helsinki, Finland. E-mail Kari.Alitalo@Helsinki.FI.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Vascular endothelial growth factor (VEGF) is an important regulator of endothelial cell proliferation, migration, and permeability during embryonic vasculogenesis as well as in physiological and pathological angiogenesis. The recently isolated VEGF-B and VEGF-C cDNAs encode novel growth factor genes of the VEGF family.
Methods and Results Southern blotting and polymerase chain reaction analysis of somatic cell hybrids and fluorescence in situ hybridization (FISH) of metaphase chromosomes were used to assess the chromosomal localization of VEGF-B and VEGF-C genes. The VEGF-B gene was found on chromosome 11q13, proximal to the cyclin D1 gene, which is amplified in a number of human carcinomas. However, VEGF-B was not amplified in several mammary carcinoma cell lines containing amplified cyclin D1. The VEGF-C gene was located on chromosome 4q34, close to the human aspartylglucosaminidase gene previously mapped to 4q34-35.
Conclusions The VEGF-B locus in 11q13 and the VEGF-C locus in 4q34 are candidate targets for mutations that lead to vascular malformations or cardiovascular diseases.
Key Words: growth substances • genes • cardiovascular diseases
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The VEGF gene encodes an angiogenic mitogen. VEGF was originally purified from several sources on the basis of its mitogenic activity and its ability to induce microvascular permeability; hence, it is also called vascular permeability factor (VPF).1 2 3 VEGF signals through two receptor tyrosine kinases, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), which are expressed specifically on endothelial cells.4 5 6 7 The VEGF-related placenta growth factor (PlGF)8 9 was recently shown to bind to VEGFR-1 with high affinity.10 PlGF was able to enhance the growth factor activity of VEGF, but it did not stimulate endothelial cells on its own, whereas naturally occurring VEGF/PlGF heterodimers were nearly as potent mitogens as VEGF homodimers for endothelial cells.11
We have recently cloned the cDNAs for two new factors structurally homologous to VEGF, designated as VEGF-B and VEGF-C.12 13 VEGF-C was identified as a ligand for the FLT4 receptor tyrosine kinase (VEGFR-3), which is related to VEGFR-1 and VEGFR-2 but does not bind VEGF.14 15 VEGFR-3 is expressed in venous and lymphatic endothelia of fetal tissues and predominantly in lymphatic endothelia of adult tissues.16 17
Here we present the localization of the VEGF-B and VEGF-C genes in human chromosomes by analysis of somatic cell hybrids and FISH.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Analysis of Somatic Cell Hybrids
A DNA panel of 24 interspecies somatic cell hybrids, which had retained one or two human chromosomes, was used for the chromosomal localization of the VEGF-B and VEGF-C genes (Bios Laboratories, Inc). Primers were designed to amplify an
1-kb fragment of the VEGF-B gene
and a 250-bp fragment of the VEGF-C gene from somatic cell hybrid DNA.
Similar fragments were obtained in polymerase chain reaction (PCR)
amplification of human genomic DNA and genomic bacteriophage 
DNA
clones containing the respective genes using these primers. The primers
and conditions for PCR were 5'-CTGCCACTCCCCACCACCGT-3' (forward),
5'-GCCATGTGTCACCTTCGCAG-3' (reverse) for VEGF-B
(denaturation/annealing/extension conditions: 95°C, 90
seconds/62°C, 45 seconds/72°C, 60 seconds) and
5'-TGAGTGATTTGTAGCTGCTGTG-3' (forward) and
5'-TATTGCAGCAACCCCCACATCT-3'
(reverse) for VEGF-C (94°C, 60 seconds/62°C, 45 seconds/72°C, 60
seconds). The PCR products were evaluated by electrophoresis in 1%
agarose gels and visualized by ethidium bromide staining in UV
light.
[
-32P]-dCTP–labeled cDNA inserts
of plasmids
representing complete VEGF-B–coding and VEGF-C–coding
domains12 13 were used as probes in Southern blotting
and
hybridization analysis of the somatic cell hybrid DNAs as
instructed by the supplier (Bios Laboratories).
Fluorescence In Situ Hybridization
Cell lines were obtained
from the American Type Culture
Collection (Rockville, Md). Purified DNA from P1 clones 6609 (VEGF-B)
and 7660 and 7661 (VEGF-C) (Genome Systems, Inc) was confirmed positive
by Southern blotting of EcoRI-digested DNA followed by
hybridization with the VEGF-B and VEGF-C cDNAs. The P1 clones were then
labeled by nick translation either with biotin-11-dUTP, biotin-14-ATP
(Sigma Chemical Co), or digoxigenin 11-dUTP (Boehringer
Mannheim GmbH) according to standard protocols. PHA-stimulated
peripheral blood lymphocyte cultures were treated with
5-bromodeoxyuridine (BrdU) at an early replicating phase to induce
G-banding.18 19 The FISH procedure was carried out in
50%
formamide/10% dextran sulfate in 2x SSC as described
elsewhere.13 20 21 Repetitive sequences
were suppressed
with 50-fold excess of Cot-1 DNA (BRL) compared with the labeled probe.
Specific hybridization signals were detected by incubating the
hybridized slides in labeled antidigoxigenin antibodies, followed by
counterstaining with 0.1 mmol/L 4,6-diamino-2-phenylindole. Probe
detection for two-color experiments was accomplished by incubating
the slides in FITC-antidigoxigenin antibodies (Sigma Chemical Co) and
Texas red–avidin (Vector Laboratories) or
rhodamine-antidigoxigenin and FITC-avidin.
Multicolor digital image analysis was used for acquisition, display, and quantification of hybridization signals of metaphase chromosomes. The system contains a PXL camera (Photometrics Inc) attached to a PowerMac 7100/Av workstation. IPLab software controls the camera operation, image acquisition, and Ludl filter wheel.22 Alternatively, an Olympus BX50 epifluorescence microscope equipped with double band-pass filters (Chromatechnology) and x100 objective (NA 1.4) was used to score the FITC and rhodamine signals. At least 50 nuclei from each cell line were scored. Overlapping nuclei and clusters of cells were ignored. A slide containing normal lymphocyte metaphase spreads and interphase nuclei was included in each experiment to control for the efficiency and specificity of the hybridization.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Chromosomal Localization of the Human VEGF-B Gene
To determine the chromosomal localization of the human VEGF-B gene, DNAs from human rodent somatic cell hybrids containing defined sets of human chromosomes were analyzed by Southern blotting and hybridization with the VEGF-B cDNA probe. Among 24 DNA samples on the hybrid panel, representing different human chromosomes, human-specific signals were observed only in hybrids that contained human chromosome 11 (data not shown). The results were confirmed by PCR of somatic cell hybrid DNA with the use of VEGF-B specific primers, in which amplified bands were obtained only from DNAs containing human chromosome 11.
A genomic P1 plasmid for VEGF-B was isolated with
specific primers and
PCR and verified by Southern blotting and hybridization with the use of
a VEGF-B–specific cDNA probe. The chromosomal localization of VEGF-B
was further studied with the use of metaphase FISH. An unambiguous
localization to 11q13 was detected. Measurements of 10 specifically
hybridized chromosome 11s demonstrated that the VEGF-B region is
located in a position that is 17% of the distance from the centromere
to the telomere of chromosome arm 11q, an area that corresponds to the
band 11q13 (Fig 1
). A second experiment was conducted in
which a biotin-labeled probe for the cyclin D1 locus, which is
known to map to the band 11q13, was cohybridized with the P1 clone for
VEGF-B. This experiment resulted in the colocalization of both signals
to the same chromosomal region (Fig 2A). Observation of
an additional 10 specifically hybridized chromosome 11s with both
clones demonstrated that the VEGF-B region is slightly centromeric of
the cyclin D1 locus. A total of 80 metaphase cells were
analyzed, and 70 exhibited specific labeling. The relatively
long distance between the cyclin D1 and VEGF-B loci was evident from
the results of double-label FISH of interphase nuclei (Fig
2B).
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Relationship of VEGF-B to 11q13 Amplicons
The chromosomal
band 11q13 is the site of frequent DNA
amplifications in human mammary carcinomas and squamous cell
carcinomas. Cyclin D1 and the EMS-1 gene encoding a cytoskeletal
protein have been suggested as two overexpressed candidate target genes
for this amplicon.23 Because VEGF-B encodes a secreted
endothelial growth factor, which could be involved in
tumorigenesis (tumor angiogenesis), we considered it of interest to
analyze the possibility of VEGF-B amplification in these tumor
cells. Interphase nuclei were therefore subjected to two-color FISH
with a VEGF-B probe and a cyclin D1 probe or a chromosome 11
centromere–specific probe. An example of such hybridization is
shown in Fig 2B
, in which chromosome 11 and two interphase
nuclei from
the breast carcinoma cell line BT-474 have been analyzed. In
these cells, the VEGF-B locus is clearly amplified in excess of the
chromosome 11 centromere. However, in a statistical comparison of the
absolute mean numbers of the target DNAs for these three probes in
breast carcinoma cell lines (Table), the VEGF-B DNA was
more than twofold amplified over chromosome 11 copy number only in the
BT-474 cell line and exceeded that of cyclin D1 DNA slightly in only
the BT-474 and MDA-436 cell lines. Thus, VEGF-B does not belong to the
core amplicon of chromosome 11q13 in breast carcinomas.
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Chromosomal Localization of the VEGF-C Gene
The VEGF-C gene
was similarly mapped first in somatic cell hybrids
to chromosome 4. Using the P1 probe for VEGF-C in FISH, we detected a
specific hybridization to the 4q34 chromosomal band in 40 of 44
metaphases (Fig 3). Double-fluorochrome
hybridization with use of a cosmid probe specific for the AGA gene
showed that VEGF-C is located just proximal to the AGA gene previously
mapped to the 4q34-35 chromosomal band (Fig 3).24
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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VEGF-B and VEGF-C are newly discovered growth factors that show close homology to VEGF.12 13 In this report, we determined the chromosomal localizations of the genes for these two novel VEGF family members. The localization of the gene for VEGF has been presented by Vincenti et al, and the placenta growth factor was previously located to chromosome 14 by analysis of somatic cell hybrids.25
The overall exon architecture of the three VEGF genes shows both similarities and differences (E. Kukk et al, personal observations, December 1996, Helsinki, Finland). Production of several different mRNAs from the primary transcript occurs in all four genes of this family.12 13 25 26 27 Expression studies by Northern blotting and hybridization show abundant VEGF-B and VEGF-C expression in heart and skeletal muscle; other tissues such as lung and kidney also express these genes.12 13 Whereas PlGF is predominantly expressed in the placenta, the expression patterns of the three VEGFs overlap in many tissues, which suggests that they may form heterodimers and interact to exert their physiological functions.
Targeted mutagenesis leading to inactivation of the VEGF receptor loci in the mouse genome has shown that VEGFR-1 is necessary for the proper organization of endothelial cells forming the vascular endothelium, while VEGFR-2 is necessary for the generation of both endothelial and hematopoietic cells.28 29 This suggests that the four genes of the VEGF family can be targets for mutations that lead to vascular malformations or cardiovascular diseases.
Note Added in Proof
The GenBank accession numbers for VEGF-B
and VEGF-C cDNAs are
U48800 and X94216, respectively.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the Finnish Cancer Organizations, the Finnish Academy, the Sigrid Juselius Foundation, the University of Helsinki, and the State Technology Development Center. We thank Tapio Tainola for excellent technical assistance.
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Footnotes |
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1 K.P. and N.H-K. contributed equally to this work.
Received December 5, 1995; revision received January 19, 1996; accepted January 23, 1996.
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