© 1995 American Heart Association, Inc.
Articles |
Hypoxia Regulates Vascular Endothelial Growth Factor Gene Expression in Endothelial Cells
Identification of a 5' Enhancer
From the Joint Program in Neonatology, Harvard Medical School and Children's Hospital, Boston, Mass.
Correspondence to Dr Stella Kourembanas, Joint Program in Neonatology, Children's Hospital, 300 Longwood Ave, Enders 9, Boston, MA 02115. E-mail kourembanas@a1.tch.harvard.edu.
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Abstract |
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Abstract Vascular endothelial growth factor (VEGF) is a potent mitogen specific for endothelial cells. Its expression is dramatically induced by low oxygen tension in a variety of cell types, and it has been suggested to be a key mediator of hypoxia-induced angiogenesis. Although VEGF action is targeted to endothelial cells, it is generally believed that these cells do not express VEGF. In addition, the mechanisms by which hypoxia regulates VEGF production remain unclear. We report in the present study that pulmonary artery endothelial cells do not express VEGF under basal conditions; however, significant VEGF mRNA levels accumulate when these cells are exposed to hypoxia. Using a DNA fragment containing human VEGF promoter sequence, we identified a 28-bp element that is necessary and sufficient to upregulate transcription in response to hypoxia. This element can act as a hypoxia-specific enhancer when placed upstream or downstream from a heterologous promoter. The enhancer includes, in addition to an octamer homologous to the hypoxia-inducible factor-1 (HIF-1) consensus, a sequence that resides 3' to the consensus. Although this sequence may not be involved in the binding of HIF-1, it is absolutely required for the enhancer activity and may be the binding site for certain constitutive binding proteins. The expression of VEGF by endothelial cells in response to hypoxia may provide an important mechanism by which endothelial cell permeability and proliferation is regulated in an autocrine manner.
Key Words: hypoxia • vascular endothelial growth factor • endothelial cells • gene regulation • enhancer
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hypoxia is an important regulator of blood vessel tone and structure. It has also been shown to be a potent stimulus of angiogenesis, a process whereby neovascularization arises from existing blood vessels. For the past several years, many growth factors have been characterized and shown to have angiogenic activities (for review, see Reference 11 ). Among these, VEGF, also known as vascular permeability factor,2 3 4 has attracted special attention and is believed to be the prime regulator of angiogenesis.5 This secreted protein has mitogenic activity that is specific for vascular endothelial cells.6 7 8 9 10 Recent studies have shown that the expression of VEGF can be induced by hypoxia,11 12 a condition that causes tumor necrosis and stimulates angiogenesis.13 14 Northern blot analysis indicated that VEGF mRNA in cultured glioma cells was dramatically increased when cells were grown under hypoxic conditions.11 In situ hybridization revealed that VEGF and its receptor mRNAs were elevated in tumor cells and that the expression was adjacent to tumor necrotic areas.11 12 These in vitro and in vivo data support a model whereby low oxygen tension associated with tumor necrosis induces the expression of VEGF, which in turn stimulates the proliferation of vascular endothelial cells in a paracrine manner, leading to the sprouting of new capillary vessels. It is generally believed that endothelial cells, the target of VEGF action, do not express VEGF under physiological or pathophysiological (such as hypoxic) conditions.
Hypoxia has been reported to regulate the expression of many genes,15 16 17 18 but the mechanisms involved are poorly understood. An activity termed HIF-1 has been shown to increase the expression of Epo in response to hypoxia,19 and more recently, HIF-1 binding sites have been identified in the genes encoding a number of glycolytic enzymes.18 However, the molecular mechanisms by which hypoxia regulates VEGF expression are not known.
In the present study, we present data showing that hypoxia increases the transcriptional rate of the VEGF gene in vascular endothelial cells. Furthermore, from a systematic analysis of the promoter, we present the identification and characterization of a 5'enhancer that is responsible for the hypoxia-induced increases in VEGF gene expression.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell Culture and Media
BPAE cells were cultured in DMEM supplemented with 10% fetal bovine serum, 2 mmol/L L-glutamine, and 0.1 mg/mL gentamicin sulfate. The cells were exposed to a normoxic environment consisting of 21% O2/5% CO2/remainder N2 or to hypoxic conditions with 95% N2/5% CO2. The measured PO2 in the media was 18 to 20 mm Hg under 0% O2 conditions and 130 mm Hg under 21% O2 conditions, as we previously reported.15 Cells were cultured at 37°C.
Plasmids and Oligonucleotides
A plasmid that contains the human VEGF 5' sequence and part of
the coding region was kindly provided by Judy A. Abraham at Scios Nova
Inc, Mountain View, Calif. A DNA fragment covering the 5' upstream
region and part of the untranslated coding sequences of VEGF was
excised from this plasmid and was used to replace the TK promoter
(Xba I–Xho I) in the plasmid
pBLCAT2.20 The resulting plasmid pVR47/CAT contains the
VEGF sequence from -2362 to +61, relative to the transcription
initiation site determined by Tischer et al21 (or from
1 to 2423 if using the numbering system of GenBank, accession No.
M63971). The plasmids that contain the truncated 5' sequences described
in Fig 2
were all generated from pVR47/CAT by restriction digestion and
religation or by unidirectional deletion using Exonuclease III from New
England Biolabs. Plasmid pRSV–ß-gal has been previously
described.22 Plasmid pCAT promoter is from Promega. The
oligonucleotide primers used to amplify different
segments in the VEGF promoter region all contain 5'-gcggatcccggg-3'
(sense strand) or 5'-gaagatct-3' (antisense strand) linked to 19 to 23
nucleotides of the native sequence. The sense strands of
the oligonucleotides used in the electrophoretic
mobility shift assays are as follows: W18
(5'-agcttGCCCTACGTGCTGTCTCAgaatt-3'), A-C'
(5'-gcggatcccgggCCACAGTGCATACGTGGGCTCagatcttc-3'), A-G
(5'-gcggatcccgggCCACAGTGCATACGTGGGCTCCAACAGGTCCTCTTagatcttc-3'), and an
NF-
B binding site (5'-agcttCAGAGGGGACTTTCCGAGAGGtcga-3'), where the
native sequences are in uppercase letters and linker sequences are in
lowercase letters.
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RNA Analysis
Total cellular RNA was prepared by guanidinium isothiocyanate
extraction from BPAE cells exposed to hypoxic (0% O2) or
normoxic (21% O2) environments for various periods. Total
RNA (15 µg per lane) was electrophoresed in 1% agarose gels
containing formaldehyde, and Northern analysis was performed.
As probes, we used an 800-bp DNA fragment, which hybridizes to the
first exon of the human VEGF gene,21 and an 800-bp
Pst I fragment of the mouse ß-actin gene. The DNA was
labeled with [
-32P]dCTP in a standard random-primed
reaction to a specific activity of 1 to 2x109 cpm/µg.
Hybridization was performed for 2 hours at 68°C in QuikHyb solution
(Stratagene), followed by low-stringency and high-stringency washes at
room temperature and 60°C, respectively.
Autoradiography was performed at -80°C for 2
days. The filters were stripped and reprobed with ß-actin to
normalize for RNA loaded.
Transfections and CAT Assays
Transfections of BPAE cells were carried out with LipofectAmine
from GIBCO-BRL according to the manufacturer's protocol. After
transfection, cells were placed in either normoxia or hypoxia.
After incubation for 24 to 48 hours, cells were lysed, and
ß-galactosidase and CAT activity were measured according to
previously described protocols.23 Normalized CAT activity
was the ratio of radioactivity (in counts per minute) of labeled
acetylchloramphenicol to the optical density units from the cleavage
product of
o-nitrophenyl-ß-D-galactopyranoside
catalyzed by ß-galactosidase.
Nuclear Extract Preparation and EMSAs
Cell nuclear extracts were prepared according to the method of
Schreiber et al,24 and total protein was quantified by
using the Bio-Rad protein assay. For EMSA, 5 µg nuclear proteins were
incubated for 10 minutes at room temperature in a 20 µL binding
mixture containing 1x HM buffer (1x HM buffer consists of 10 mmol/L
HEPES, pH 7.9, 0.5 mmol/L MgCl2, 0.1 mmol/L EDTA,
and 5% glycerol), 100 to 130 mmol/L KCl, 1 µg
polydeoxyinosinic-deoxycytidylic acid, and in some cases competitor
oligonucleotides. Radiolabeled
oligonucleotides (22 000 cpm) were then added, and the
incubation was continued for 20 minutes. The binding mixture was
fractionated on a 4% polyacrylamide gel in 0.5x TBE (1x TBE
consists of 89 mmol/L Tris base, 89 mmol/L boric acid, and 5 mmol/L
EDTA) at 4°C. After it was dried, the gel was autoradiographed at
-80°C.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hypoxia Increases VEGF mRNA Levels in Endothelial Cells
BPAE cells were exposed to 0% O2 or to an ambient environment for 18 hours. Northern blot analysis of total RNA showed a single 3.7-kb VEGF message in RNA isolated from hypoxic endothelial cells, but no signal was detected in normoxic cell RNA (Fig 1
). ß-Actin mRNA levels were
not altered by hypoxia under these conditions. VEGF mRNA levels
increased by 6 hours of hypoxia, when the
PO2 is 
60 mm Hg,16 and
remained elevated at 48 hours (data not shown). The heavy metals
CoCl2 and NiCl2, known to have the same
effects on gene expression as hypoxia, also increased VEGF mRNA
levels in endothelial cells. CdCl2,
on the other hand, had no effect on VEGF mRNA (authors' unpublished
data, 1994).
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Hypoxia Increases the Transcriptional Rate of the
VEGF Gene
To examine whether the increases in VEGF mRNA in
endothelial cells are regulated at the transcriptional
level, we constructed a plasmid in which the promoter of the human VEGF
gene was fused to the reporter CAT gene by replacing the TK promoter in
plasmid pBLCAT2 with that of VEGF (Fig 2
). The resulting
plasmid pVR47/CAT contains VEGF sequences from -2362 to +61 (relative
to the transcription initiation site, see "Materials and
Methods"). This plasmid was then transfected into BPAE cells, which
were incubated under either hypoxic (0% O2) or normoxic
(21% O2) conditions. Plasmid pRSV–ß-gal, containing the
ß-galactosidase gene under the control of the Rous sarcoma virus long
terminal repeat, was cotransfected into BPAE cells. After incubation,
cells were lysed, and CAT activity was measured and normalized to that
of ß-galactosidase. As shown in Fig 2, CAT activity was induced
5.5-fold by hypoxia. These results indicate the presence of a
positive hypoxia response element in the 5' region of the VEGF
gene that regulates its transcription.
Delineation of the Hypoxia Response Element of
VEGF
A series of deletions were made upstream from the transcription
initiation site in the plasmid pVR47/CAT (Fig 2). These new plasmids
were transfected into BPAE cells, and CAT activity was determined. As
shown in Fig 2, hypoxia inducibility was retained until the
deletions were extended to -795 [plasmid pV(-795)/CAT]. Further
deletions resulted in loss of a hypoxic response; however, the basal
activity was retained and was similar in all constructs. Since plasmid
pV(-985)/CAT still retains the hypoxia inducibility and is
190-bp longer in 5' sequence than pV(-795)/CAT, we postulated that the
hypoxia response element may reside in this 190-bp fragment.
Indeed, when this 190-bp fragment (-985 to -790) was excised from the
surrounding sequence and inserted in front of the TK promoter in
plasmid pBLCAT2, it provided a strong (8.4-fold) induction on CAT gene
expression (Fig 3).
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Further localization of this element was carried out by amplifying
different segments within the 190-bp region by polymerase chain
reaction and testing their ability to increase CAT gene expression in
response to hypoxia. The smallest region that still provides
hypoxia inducibility (4.7-fold) is a 28-bp fragment (-978 to
-951) close to the 5' end of the 190-bp sequence (Fig 3).
To investigate whether the hypoxia regulatory element has the characteristics of a classic enhancer, we inserted the 28-bp fragment mentioned above into the BamHI site upstream from the TK promoter in pBLCAT2 in both orientations. The resulting plasmids both showed a 4.7-fold induction by hypoxia. We have also inserted a second fragment (-985 to -863) in either orientation downstream from the CAT gene and obtained similar results (data not shown), demonstrating that the hypoxia response element is an enhancer.
cis-Acting Elements in the VEGF Enhancer in Addition to
the HIF-1 Binding Consensus Are Needed for the Stimulation of the VEGF
Gene by Hypoxia
A recent study by Semenza et al18 has shown that the
HIF-1 recognition sequence contained in the hypoxia response
element of the Epo gene is conserved in a number of glycolytic enzyme
genes that are hypoxia inducible. The consensus in these
elements is (G/C/T)ACGTGC(G/T) (see Fig 4). In
sequence comparison analysis, we have found a short region
(underlined in Fig 4) in the VEGF hypoxia response element that
is highly homologous to this consensus. The sequence of this region is
TACGTGGG and differs from the consensus in the seventh
nucleotide, which is a G in the VEGF enhancer
(double-underlined) and a conserved C in the Epo and glycolytic enzyme
genes. We have made several deletions in the 35-bp fragment containing
the minimal 28-bp hypoxia response element and tested their
function in transfection experiments (Fig 4). We observed that the
disruption of the core HIF-1 binding sequence (construct V1714)
eliminated hypoxia inducibility. Interestingly, we found that
the downstream sequence (3' to the core) is also important, because the
replacement of this region with linker or vector sequences without
changing the core either dramatically reduced the hypoxic induction
(construct V1316b) or abolished it completely (construct V1318).
Therefore, critical elements (TCCTCTT) in the region 3' to the
consensus are required for VEGF enhancer function.
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A Hypoxia-Inducible Factor Binds to the
Enhancer
An enhancer element exerts its function through the binding of a
trans-acting factor. To demonstrate the presence of such a
factor, we have radiolabeled fragment A-G (see Fig 4) and performed in
vitro binding followed by EMSA. As shown in Fig 5A, a
distinct band was induced in nuclear extracts isolated from
hypoxia-treated cells (lane 3) but not by normoxia-treated
cells (lane 2), indicating the presence of an inducible
trans-acting factor. Competition EMSA was carried out by
incubating nuclear proteins with labeled fragment A-G in the presence
of several unlabeled competitors. The binding was competed by
increasing amounts (20-, 100-, and 500-fold excess) of unlabeled
fragment A-G (lanes 4 through 6) but not by the same amounts of an
arbitrary oligonucleotide (in this case, an NF-B
binding sequence) (lanes 7 through 9), indicating that the binding
activity is specific for the VEGF enhancer.
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The only hypoxia-inducible factor that has been investigated so
far is the one that binds to the enhancer region of the Epo gene, named
HIF-1.19 25 26 To explore potential common mechanisms of
transcriptional regulation by hypoxia between VEGF and Epo,
competition EMSA was carried out. A double-stranded
oligonucleotide competitor (W18), which is contained in
the Epo enhancer and has been shown to bind to HIF-1,19
was added to the cell nuclear extract before the addition of labeled
VEGF enhancer (fragment A-G). The competitor was in 20-, 100-, 500-,
and 1000-fold excess to the labeled VEGF enhancer (Fig 5A, lanes 10
through 13). The EMSA results showed that W18 can compete with labeled
A-G for nuclear factors, although to a lesser extent than the unlabeled
A-G fragment. Thus, factors binding to the VEGF enhancer may be related
to, if not the same as, the component(s) that binds to the Epo
enhancer.
Interestingly, a 21-bp fragment (contained in construct V1318), which
retains an intact HIF-1 site but has a deletion of the sequence 3' to
the consensus, allowed for hypoxia-induced binding to occur in
vitro (Fig 5B). Since this fragment does not have a function in the
absence of the downstream sequence (Fig 4), the binding of HIF-1 (or a
similar factor) to the VEGF enhancer is not sufficient to provide
hypoxia inducibility.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hypoxia is a recognized stimulus for blood vessel remodeling, altered cellular permeability, and the process of angiogenesis. VEGF is dramatically induced by hypoxia in a number of tumor cells as well as in fibroblasts and smooth muscle cells.11 12 27 Although endothelial cells are the target cells of VEGF action, they are not known to produce VEGF. We report in the present study that pulmonary artery endothelial cells are capable of expressing VEGF under conditions of hypoxia by increasing the transcriptional rate of the gene.
We have identified a hypoxia-responsive enhancer in the promoter region of the human VEGF gene, which includes a 28-bp element that is sufficient to mediate the upregulation of VEGF gene transcription. Gel retardation assays revealed a hypoxia-inducible factor that can bind to this element. In addition, we showed that oligonucleotides corresponding to the Epo enhancer sequence could compete for the binding of this element, suggesting that the binding protein for these two may be related.
Semenza et al18 recently reported the HIF-1 binding
sequence originally described in the Epo enhancer to be conserved in
several genes encoding enzymes in the glycolytic pathway. The consensus
in these elements is (G/C/T)ACGTGC(G/T). Interestingly, a
computer-aided search in the VEGF promoter region has revealed several
sequences that closely resemble the HIF-1 binding consensus. One of
them, CGCACGTA, at position -313 (or 2050 if using the numbering
system of GenBank, accession number M63971), is 100% homologous to
this consensus when read from the antisense strand. However, VEGF
promoter constructs containing this sequence, but lacking the 28-bp
element, did not show any hypoxia inducibility in
endothelial cells [plasmids pV(-795)/CAT and
pV(-416)/CAT; see Fig 2]. Furthermore, in our deletion experiments,
we demonstrated that the replacement of nucleotides 3' to
the consensus in the VEGF element (constructs V1316b and V1318; see Fig 4) resulted in either a dramatically reduced or a completely abolished
induction by hypoxia despite the presence of the intact HIF-1
consensus sequence (Fig 4). Therefore, it appears that the VEGF
enhancer function requires not only the conserved HIF-1 recognition
sequence but also its flanking context, which may be bound by other
factors. Further dissection of the VEGF enhancer is in progress.
Previous studies have indicated that the expression of AP-1 proteins c-jun and c-fos are upregulated by hypoxia.28 29 Since there are three potential AP-1 binding sites in the promoter region of VEGF,21 it has been speculated that hypoxia induction of VEGF expression might be mediated by AP-1. Our results suggest that the AP-1 site may not be a necessary element for hypoxic regulation, because the 28-bp enhancer is sufficient to provide hypoxia response when inserted in front of a reporter gene. However, to completely exclude the possibility of the involvement of AP-1 (or any other suspected elements in the promoter) in hypoxic regulation, it is necessary to test a construct in which only the enhancer is mutated and all the surrounding sequences are intact.
The identification of a 5' enhancer that upregulates VEGF transcription presents a molecular mechanism that links hypoxia and angiogenesis. However, there may be other mechanisms (eg, other transcriptional elements or posttranscriptional events) that also contribute to the hypoxic regulation of VEGF expression. Minchenko et al30 found two regions in the human VEGF gene that were shown to be hypoxia responsive in transient transfection experiments using HeLa cells. The enhancer identified in the present study using endothelial cells is distinct from the above-reported regions in experiments using the HeLa cell system. It is possible that more than one element contributes to the hypoxic induction of the human VEGF gene. Additionally, the relative contributions of each element may vary according to cell type, such that the 28-bp enhancer identified in the present study may be important in the hypoxic response of endothelial cells, whereas the regions reported by Minchenko et al may play a role in regulating VEGF expression in HeLa cells. According to our findings, the expression of VEGF by hypoxic endothelial cells implicates these cells not only as passive responders to this potent mitogen but also as possible regulators of their growth and permeability in an autocrine manner.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Liu was supported by Individual National Research Service Award HL-09008. Dr Kourembanas was supported in part by a grant from the American Heart Association and by National Institutes of Health grant P50 HL-46491. We thank Dr Judy A. Abraham for providing plasmids, Dr S. Alex Mitsialis for critical reading of the manuscript, and Kelly Ames for her secretarial assistance.
Received May 26, 1995; accepted July 10, 1995.
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References |
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|---|
1. Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992;267:10931-10934.
2. Connolly DT, Heuvelman 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;84:1470-1478.
3.
Connolly DT, Olander JV, Heuvelman D, Nelson R,
Monsell R, Siegel N, Haymore BL, Leimgruber R, Feder J. Human
vascular permeability factor: isolation from U937 cells.
J Biol Chem. 1989;264:20017-20024.
4. Connolly DT. Vascular permeability factor: a unique regulator of blood vessel function. J Cell Biochem. 1991;47:219-223. [Medline] [Order article via Infotrieve]
5. Klagsbrun M, Soker S. VEGF/VPF: the angiogenesis factor found? Curr Biol. 1993;3:699-702. [Medline] [Order article via Infotrieve]
6.
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara
N. Vascular endothelial growth factor is a
secreted angiogenic mitogen. Science. 1989;246:1306-1309.
7. Jakeman LB, Winer J, Bennett GL, Altar A, Ferrara N. Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest. 1992;89:244-253.
8.
Gospodarowicz D, Abraham JA, Schilling J.
Isolation and characterization of a vascular
endothelial cell mitogen produced by pituitary-derived
folliculo stellate cells. Proc Natl Acad Sci
U S A. 1989;86:7311-7315.
9. Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989;161:851-858. [Medline] [Order article via Infotrieve]
10.
Conn G, Soderman DD, Schaeffer MT, Wile M, Hatcher VB,
Thomas KA. Purification of a glycoprotein
vascular endothelial cell mitogen from a rat
glioma-derived cell line. Proc Natl Acad Sci
U S A. 1990;87:1323-1327.
11. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;359:843-845. [Medline] [Order article via Infotrieve]
12. Plate KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992;359:845-848. [Medline] [Order article via Infotrieve]
13.
Adair TH, Gay WJ, Montani JP. Growth regulation
of the vascular system: evidence for a metabolic
hypothesis. Am J Physiol. 1990;259:R393-R404.
14.
Knighton DR, Hunt TK, Scheuenstuhl H, Halliday BJ, Werb
Z, Banda MJ. Oxygen tension regulates the expression of
angiogenesis factor by macrophages. Science. 1983;221:1283-1285.
15. Kourembanas S, Hannan RL, Faller DV. Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. J Clin Invest. 1990;86:670-674.
16. Kourembanas S, Marsden PA, McQuillan LP, Faller DV. Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J Clin Invest. 1991;88:1054-1057.
17. Rocha-Singh KJ, Honbo NY, Karliner JS. Hypoxia and glucose independently regulate the ß-adrenergic receptor-adenylate cyclase system in cardiac myocytes. J Clin Invest. 1991;88:204-213.
18.
Semenza GL, Roth PH, Fang H-M, Wang GL.
Transcriptional regulation of genes encoding glycolytic enzymes
by hypoxia-inducible factor 1. J Biol
Chem. 1994;269:23757-23763.
19.
Semenza GL, Wang GL. A nuclear factor induced by
hypoxia via de novo protein synthesis binds to the human
erythropoietin gene enhancer at a site required for transcriptional
activation. Mol Cell Biol. 1992;12:5447-5454.
20.
Luckow B, Schutz G. CAT constructions with
multiple unique restriction sites for the functional analysis
of eukaryotic promoters and regulatory elements.
Nucleic Acids Res. 1987;15:5490.
21.
Tischer E, Mitchell R, Hartman T, Silva M,
Gospodarowicz D, Fiddes JC, Abraham JA. The human gene for
vascular endothelial growth factor.
J Biol Chem. 1991;266:11947-11954.
22.
Edlund T, Walker MD, Barr PJ, Rutter WJ.
Cell-specific expression of the rat insulin gene: evidence for
role of two distinct 5' flanking elements. Science. 1985;230:912-916.
23. Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1989.
24.
Schreiber E, Matthias P, Muller MM, Schaffner W.
Rapid detection of octamer binding proteins with
`mini-extracts,' prepared from a small number of cells.
Nucleic Acids Res. 1989;17:6419.
25.
Wang GL, Semenza GL. Characterization of
hypoxia-inducible factor 1 and regulation of DNA binding
activity by hypoxia. J Biol Chem. 1993;268:21513-21518.
26.
Wang GL, Semenza GL. General involvement of
hypoxia-inducible factor 1 in transcriptional response to
hypoxia. Proc Natl Acad Sci U S A. 1993;90:4304-4308.
27.
Brogi E, Wu T, Namiki A, Isner JM. Indirect
angiogenic cytokines upregulate VEGF and bFGF gene expression
in vascular smooth muscle cells, whereas hypoxia upregulates
VEGF expression only. Circulation. 1994;90:649-652.
28.
Goldberg MA, Schneider TJ. Similarities between
the oxygen-sensing mechanisms regulating the expression of vascular
endothelial growth factor and erythropoietin.
J Biol Chem. 1994;269:4355-4359.
29.
Ausserer WA, Bourrat-Floeck B, Green CJ, Laderoute KR,
Sutherland RM. Regulation of c-jun expression during
hypoxic and low-glucose stress. Mol Cell Biol. 1994;14:5032-5042.
30. Minchenko A, Salceda S, Bauer T, Caro J. Hypoxia regulatory elements of the human vascular endothelial growth factor gene. Cell Mol Biol Res. 1994;40:35-39.[Medline] [Order article via Infotrieve]
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 J.-X. Chen and A. Stinnett Ang-1 Gene Therapy Inhibits Hypoxia-Inducible Factor-1{alpha} (HIF-1{alpha})-Prolyl-4-Hydroxylase-2, Stabilizes HIF-1{alpha} Expression, and Normalizes Immature Vasculature in db/db Mice Diabetes, December 1, 2008; 57(12): 3335 - 3343. [Abstract] [Full Text] [PDF]
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 Y. Zhang, N. Zhang, B. Dai, M. Liu, R. Sawaya, K. Xie, and S. Huang FoxM1B Transcriptionally Regulates Vascular Endothelial Growth Factor Expression and Promotes the Angiogenesis and Growth of Glioma Cells Cancer Res., November 1, 2008; 68(21): 8733 - 8742. [Abstract] [Full Text] [PDF]
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 Y. Chen, Y.-q. Doughman, S. Gu, A. Jarrell, S.-i. Aota, A. Cvekl, M. Watanabe, S. L. Dunwoodie, R. S. Johnson, V. van Heyningen, et al. Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis Development, September 1, 2008; 135(17): 2939 - 2948. [Abstract] [Full Text] [PDF]
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 M.-C. Lauzier, G. A. Robitaille, D. A. Chan, A. J. Giaccia, and D. E. Richard (2R)-[(4-Biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide (BiPS), a Matrix Metalloprotease Inhibitor, Is a Novel and Potent Activator of Hypoxia-Inducible Factors Mol. Pharmacol., July 1, 2008; 74(1): 282 - 288. [Abstract] [Full Text] [PDF]
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 B. A. Bryan, T. E. Walshe, D. C. Mitchell, J. S. Havumaki, M. Saint-Geniez, A. S. Maharaj, A. E. Maldonado, and P. A. D'Amore Coordinated Vascular Endothelial Growth Factor Expression and Signaling During Skeletal Myogenic Differentiation Mol. Biol. Cell, March 1, 2008; 19(3): 994 - 1006. [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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 F. Vumbaca, K. N. Phoenix, D. Rodriguez-Pinto, D. K. Han, and K. P. Claffey Double-Stranded RNA-Binding Protein Regulates Vascular Endothelial Growth Factor mRNA Stability, Translation, and Breast Cancer Angiogenesis Mol. Cell. Biol., January 15, 2008; 28(2): 772 - 783. [Abstract] [Full Text] [PDF]
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R. Amarilio, S. V. Viukov, A. Sharir, I. Eshkar-Oren, R. S. Johnson, and E. Zelzer HIF1{alpha} regulation of Sox9 is necessary to maintain differentiation of hypoxic prechondrogenic cells during early skeletogenesis Development, November 1, 2007; 134(21): 3917 - 3928. [Abstract] [Full Text] [PDF]
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 M. Milkiewicz, J. L. Doyle, T. Fudalewski, E. Ispanovic, M. Aghasi, and T. L. Haas HIF-1{alpha} and HIF-2{alpha} play a central role in stretch-induced but not shear-stress-induced angiogenesis in rat skeletal muscle J. Physiol., September 1, 2007; 583(2): 753 - 766. [Abstract] [Full Text] [PDF]
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W.-L. Yeh, D.-Y. Lu, C.-J. Lin, H.-C. Liou, and W.-M. Fu Inhibition of Hypoxia-Induced Increase of Blood-Brain Barrier Permeability by YC-1 through the Antagonism of HIF-1{alpha} Accumulation and VEGF Expression Mol. Pharmacol., August 1, 2007; 72(2): 440 - 449. [Abstract] [Full Text] [PDF]
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B. Drogat, P. Auguste, D. T. Nguyen, M. Bouchecareilh, R. Pineau, J. Nalbantoglu, R. J. Kaufman, E. Chevet, A. Bikfalvi, and M. Moenner IRE1 Signaling Is Essential for Ischemia-Induced Vascular Endothelial Growth Factor-A Expression and Contributes to Angiogenesis and Tumor Growth In vivo Cancer Res., July 15, 2007; 67(14): 6700 - 6707. [Abstract] [Full Text] [PDF]
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 T. R. Grover, T. M. Asikainen, J. P. Kinsella, S. H. Abman, and C. W. White Hypoxia-inducible factors HIF-1{alpha} and HIF-2{alpha} are decreased in an experimental model of severe respiratory distress syndrome in preterm lambs Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1345 - L1351. [Abstract] [Full Text] [PDF]
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J. E. Fish, C. C. Matouk, E. Yeboah, S. C. Bevan, M. Khan, K. Patil, M. Ohh, and P. A. Marsden Hypoxia-inducible Expression of a Natural cis-Antisense Transcript Inhibits Endothelial Nitric-oxide Synthase J. Biol. Chem., May 25, 2007; 282(21): 15652 - 15666. [Abstract] [Full Text] [PDF]
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 T. D. Ardizzone, X. Zhan, B. P. Ander, and F. R. Sharp Src Kinase Inhibition Improves Acute Outcomes After Experimental Intracerebral Hemorrhage Stroke, May 1, 2007; 38(5): 1621 - 1625. [Abstract] [Full Text] [PDF]
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 G. C. Schatteman, M. Dunnwald, and C. Jiao Biology of bone marrow-derived endothelial cell precursors Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H1 - H18. [Abstract] [Full Text] [PDF]
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M. Ramanathan, G. Pinhal-Enfield, I. Hao, and S. J. Leibovich Synergistic Up-Regulation of Vascular Endothelial Growth Factor (VEGF) Expression in Macrophages by Adenosine A2A Receptor Agonists and Endotoxin Involves Transcriptional Regulation via the Hypoxia Response Element in the VEGF Promoter Mol. Biol. Cell, January 1, 2007; 18(1): 14 - 23. [Abstract] [Full Text] [PDF]
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J.-J. Briere, J. Favier, A.-P. Gimenez-Roqueplo, and P. Rustin Tricarboxylic acid cycle dysfunction as a cause of human diseases and tumor formation Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1114 - C1120. [Abstract] [Full Text] [PDF]
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A. T. Argaw, Y. Zhang, B. J. Snyder, M.-L. Zhao, N. Kopp, S. C. Lee, C. S. Raine, C. F. Brosnan, and G. R. John IL-1beta Regulates Blood-Brain Barrier Permeability via Reactivation of the Hypoxia-Angiogenesis Program J. Immunol., October 15, 2006; 177(8): 5574 - 5584. [Abstract] [Full Text] [PDF]
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 D. G. Peters, W. Ning, T. J. Chu, C. J. Li, and A. M. K. Choi Comparative SAGE analysis of the response to hypoxia in human pulmonary and aortic endothelial cells Physiol Genomics, September 14, 2006; 26(2): 99 - 108. [Abstract] [Full Text] [PDF]
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 G. M. Woldemichael, J. R. Vasselli, R. S. Gardella, T. C. Mckee, W. M. Linehan, and J. B. McMahon Development of a Cell-Based Reporter Assay for Screening of Inhibitors of Hypoxia-Inducible Factor 2-Induced Gene Expression J Biomol Screen, September 1, 2006; 11(6): 678 - 687. [Abstract] [PDF]
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 |
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 C. Wang, D. Weihrauch, D. A. Schwabe, M. Bienengraeber, D. C. Warltier, J. R. Kersten, P. F. Pratt Jr, and P. S. Pagel Extracellular signal-regulated kinases trigger isoflurane preconditioning concomitant with upregulation of hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in rats. Anesth. Analg., August 1, 2006; 103(2): 281 - 8, table of contents. [Abstract] [Full Text] [PDF]
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G. Liu, J. Roy, and E. A. Johnson Identification and function of hypoxia-response genes in Drosophila melanogaster Physiol Genomics, March 13, 2006; 25(1): 134 - 141. [Abstract] [Full Text] [PDF]
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C. Kaur, V. Sivakumar, and W. S. Foulds Early response of neurons and glial cells to hypoxia in the retina. Invest. Ophthalmol. Vis. Sci., March 1, 2006; 47(3): 1126 - 1141. [Abstract] [Full Text] [PDF]
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S. Kajimura, K. Aida, and C. Duan Understanding Hypoxia-Induced Gene Expression in Early Development: In Vitro and In Vivo Analysis of Hypoxia-Inducible Factor 1-Regulated Zebra Fish Insulin-Like Growth Factor Binding Protein 1 Gene Expression Mol. Cell. Biol., February 1, 2006; 26(3): 1142 - 1155. [Abstract] [Full Text] [PDF]
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 C. E. Mascio, A. K. Olison, J. C. Ralphe, R. J. Tomanek, T. D. Scholz, and J. L. Segar Myocardial vascular and metabolic adaptations in chronically anemic fetal sheep Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1736 - R1745. [Abstract] [Full Text] [PDF]
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 R. H. Wenger, D. P. Stiehl, and G. Camenisch Integration of Oxygen Signaling at the Consensus HRE Sci. Signal., October 18, 2005; 2005(306): re12 - re12. [Abstract] [Full Text] [PDF]
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 N. Yamada, Y. Horikawa, N. Oda, K. Iizuka, N. Shihara, S. Kishi, and J. Takeda Genetic Variation in the Hypoxia-Inducible Factor-1{alpha} Gene Is Associated with Type 2 Diabetes in Japanese J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5841 - 5847. [Abstract] [Full Text] [PDF]
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M. Milkiewicz and T. L. Haas Effect of mechanical stretch on HIF-1{alpha} and MMP-2 expression in capillaries isolated from overloaded skeletal muscles: laser capture microdissection study Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1315 - H1320. [Abstract] [Full Text] [PDF]
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 C. D. Kamat, D. E. Green, S. Curilla, L. Warnke, J. W. Hamilton, S. Sturup, C. Clark, and M. A. Ihnat Role of HIF Signaling on Tumorigenesis in Response to Chronic Low-Dose Arsenic Administration Toxicol. Sci., August 1, 2005; 86(2): 248 - 257. [Abstract] [Full Text] [PDF]
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K. D. Cowden Dahl, S. E. Robertson, V. M. Weaver, and M. C. Simon Hypoxia-inducible Factor Regulates {alpha}v{beta}3 Integrin Cell Surface Expression Mol. Biol. Cell, April 1, 2005; 16(4): 1901 - 1912. [Abstract] [Full Text] [PDF]
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H. Yun, M. Lee, S.-S. Kim, and J. Ha Glucose Deprivation Increases mRNA Stability of Vascular Endothelial Growth Factor through Activation of AMP-activated Protein Kinase in DU145 Prostate Carcinoma J. Biol. Chem., March 18, 2005; 280(11): 9963 - 9972. [Abstract] [Full Text] [PDF]
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 L. K. Kairaitis, Y. Wang, M. Gassmann, Y.-C. Tay, and D. C. H. Harris HIF-1{alpha} expression follows microvascular loss in advanced murine adriamycin nephrosis Am J Physiol Renal Physiol, January 1, 2005; 288(1): F198 - F206. [Abstract] [Full Text] [PDF]
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 A. H. Box and D. J. Demetrick Cell cycle kinase inhibitor expression and hypoxia-induced cell cycle arrest in human cancer cell lines Carcinogenesis, December 1, 2004; 25(12): 2325 - 2335. [Abstract] [Full Text] [PDF]
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 M. Mura, C. C. dos Santos, D. Stewart, and M. Liu Vascular endothelial growth factor and related molecules in acute lung injury J Appl Physiol, November 1, 2004; 97(5): 1605 - 1617. [Abstract] [Full Text] [PDF]
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 P. B. Freeburg and D. R. Abrahamson Divergent Expression Patterns for Hypoxia-Inducible Factor-1{beta} and Aryl Hydrocarbon Receptor Nuclear Transporter-2 in Developing Kidney J. Am. Soc. Nephrol., October 1, 2004; 15(10): 2569 - 2578. [Abstract] [Full Text] [PDF]
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D. L. Ramirez-Bergeron, A. Runge, K. D. C. Dahl, H. J. Fehling, G. Keller, and M. C. Simon Hypoxia affects mesoderm and enhances hemangioblast specification during early development Development, September 15, 2004; 131(18): 4623 - 4634. [Abstract] [Full Text] [PDF]
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 S. W. Han, G. W. Kim, J. S. Seo, S. J. Kim, K. H. Sa, J. Y. Park, J. Lee, S. Y. Kim, J. J. Goronzy, C. M. Weyand, et al. VEGF gene polymorphisms and susceptibility to rheumatoid arthritis Rheumatology, September 1, 2004; 43(9): 1173 - 1177. [Abstract] [Full Text] [PDF]
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 N. Ferrara Vascular Endothelial Growth Factor: Basic Science and Clinical Progress Endocr. Rev., August 1, 2004; 25(4): 581 - 611. [Abstract] [Full Text] [PDF]
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W. Ning, T. J. Chu, C. J. Li, A. M. K. Choi, and D. G. Peters Genome-wide analysis of the endothelial transcriptome under short-term chronic hypoxia Physiol Genomics, June 17, 2004; 18(1): 70 - 78. [Abstract] [Full Text] [PDF]
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 C. Dai, R. E. McAninch, and R. E. Sutton Identification of Synthetic Endothelial Cell-Specific Promoters by Use of a High-Throughput Screen J. Virol., June 15, 2004; 78(12): 6209 - 6221. [Abstract] [Full Text] [PDF]
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A M Jubb, T Q Pham, A M Hanby, G D Frantz, F V Peale, T D Wu, H W Koeppen, and K J Hillan Expression of vascular endothelial growth factor, hypoxia inducible factor 1{alpha}, and carbonic anhydrase IX in human tumours J. Clin. Pathol., May 1, 2004; 57(5): 504 - 512. [Abstract] [Full Text] [PDF]
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|
 J. A. Fogarty, J. M. Muller-Delp, M. D. Delp, M. L. Mattox, M. H. Laughlin, and J. L. Parker Exercise Training Enhances Vasodilation Responses to Vascular Endothelial Growth Factor in Porcine Coronary Arterioles Exposed to Chronic Coronary Occlusion Circulation, February 10, 2004; 109(5): 664 - 670. [Abstract] [Full Text] [PDF]
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 C. Y. Cheung Vascular Endothelial Growth Factor Activation of Intramembranous Absorption: A Critical Pathway for Amniotic Fluid Volume Regulation Reproductive Sciences, February 1, 2004; 11(2): 63 - 74. [Abstract] [PDF]
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A. L. Goerges and M. A. Nugent pH Regulates Vascular Endothelial Growth Factor Binding to Fibronectin: A MECHANISM FOR CONTROL OF EXTRACELLULAR MATRIX STORAGE AND RELEASE J. Biol. Chem., January 16, 2004; 279(3): 2307 - 2315. [Abstract] [Full Text] [PDF]
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I. Fantozzi, S. Zhang, O. Platoshyn, C. V. Remillard, R. T. Cowling, and J. X.-J. Yuan Hypoxia increases AP-1 binding activity by enhancing capacitative Ca2+ entry in human pulmonary artery endothelial cells Am J Physiol Lung Cell Mol Physiol, December 1, 2003; 285(6): L1233 - L1245. [Abstract] [Full Text] [PDF]
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M. D. Wheeler, O. M. Smutney, and R. J. Samulski Secretion of Extracellular Superoxide Dismutase From Muscle Transduced With Recombinant Adenovirus Inhibits the Growth of B16 Melanomas in Mice Mol. Cancer Res., October 1, 2003; 1(12): 871 - 881. [Abstract] [Full Text] [PDF]
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E. M. Conway, F. Zwerts, V. Van Eygen, A. DeVriese, N. Nagai, W. Luo, and D. Collen Survivin-Dependent Angiogenesis in Ischemic Brain: Molecular Mechanisms of Hypoxia-Induced Up-Regulation Am. J. Pathol., September 1, 2003; 163(3): 935 - 946. [Abstract] [Full Text] [PDF]
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D. Mottet, V. Dumont, Y. Deccache, C. Demazy, N. Ninane, M. Raes, and C. Michiels Regulation of Hypoxia-inducible Factor-1{alpha} Protein Level during Hypoxic Conditions by the Phosphatidylinositol 3-Kinase/Akt/Glycogen Synthase Kinase 3{beta} Pathway in HepG2 Cells J. Biol. Chem., August 15, 2003; 278(33): 31277 - 31285. [Abstract] [Full Text] [PDF]
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 |
|
 N. J. Mabjeesh, M. T. Willard, C. E. Frederickson, H. Zhong, and J. W. Simons Androgens Stimulate Hypoxia-inducible Factor 1 Activation via Autocrine Loop of Tyrosine Kinase Receptor/Phosphatidylinositol 3'-Kinase/Protein Kinase B in Prostate Cancer Cells Clin. Cancer Res., July 1, 2003; 9(7): 2416 - 2425. [Abstract] [Full Text] [PDF]
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 M. Ramanathan, A. Giladi, and S. J. Leibovich Regulation of Vascular Endothelial Growth Factor Gene Expression in Murine Macrophages by Nitric Oxide and Hypoxia Experimental Biology and Medicine, June 1, 2003; 228(6): 697 - 705. [Abstract] [Full Text] [PDF]
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M. Hanaoka, Y. Droma, A. Naramoto, T. Honda, T. Kobayashi, and K. Kubo Vascular endothelial growth factor in patients with high-altitude pulmonary edema J Appl Physiol, May 1, 2003; 94(5): 1836 - 1840. [Abstract] [Full Text] [PDF]
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|
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P. B. Freeburg, B. Robert, P. L. St. John, and D. R. Abrahamson Podocyte Expression of Hypoxia-Inducible Factor (HIF)-1 and HIF-2 during Glomerular Development J. Am. Soc. Nephrol., April 1, 2003; 14(4): 927 - 938. [Abstract] [Full Text] [PDF]
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 |
|
 S. J. Welsh, R. R. Williams, A. Birmingham, D. J. Newman, D. L. Kirkpatrick, and G. Powis The Thioredoxin Redox Inhibitors 1-Methylpropyl 2-Imidazolyl Disulfide and Pleurotin Inhibit Hypoxia-induced Factor 1{alpha} and Vascular Endothelial Growth Factor Formation Mol. Cancer Ther., March 1, 2003; 2(3): 235 - 243. [Abstract] [Full Text] [PDF]
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 K. Reisinger, R. Kaufmann, and J. Gille Increased Sp1 phosphorylation as a mechanism of hepatocyte growth factor (HGF/SF)-induced vascular endothelial growth factor (VEGF/VPF) transcription J. Cell Sci., January 15, 2003; 116(2): 225 - 238. [Abstract] [Full Text] [PDF]
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|
 S. RODRIGUES, E. VAN AKEN, S. VAN BOCXLAER, S. ATTOUB, Q.-D. NGUYEN, E. BRUYNEEL, B. R. WESTLEY, F. E. B. MAY, L. THIM, M. MAREEL, et al. Trefoil peptides as proangiogenic factors in vivo and in vitro: implication of cyclooxygenase-2 and EGF receptor signaling FASEB J, January 1, 2003; 17(1): 7 - 16. [Abstract] [Full Text] [PDF]
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|
N. Gao, B.-H. Jiang, S. S. Leonard, L. Corum, Z. Zhang, J. R. Roberts, J. Antonini, J. Z. Zheng, D. C. Flynn, V. Castranova, et al. p38 Signaling-mediated Hypoxia-inducible Factor 1alpha and Vascular Endothelial Growth Factor Induction by Cr(VI) in DU145 Human Prostate Carcinoma Cells J. Biol. Chem., November 15, 2002; 277(47): 45041 - 45048. [Abstract] [Full Text] [PDF]
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|
K. A. Sanders, K. M. Sundar, L. He, B. Dinger, S. Fidone, and J. R. Hoidal Role of components of the phagocytic NADPH oxidase in oxygen sensing J Appl Physiol, October 1, 2002; 93(4): 1357 - 1364. [Abstract] [Full Text] [PDF]
|
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|
|
D. Baatar, M. K. Jones, K. Tsugawa, R. Pai, W. S. Moon, G. Y. Koh, I. Kim, S. Kitano, and A. S. Tarnawski Esophageal Ulceration Triggers Expression of Hypoxia-Inducible Factor-1{alpha} and Activates Vascular Endothelial Growth Factor Gene : Implications for Angiogenesis and Ulcer Healing Am. J. Pathol., October 1, 2002; 161(4): 1449 - 1457. [Abstract] [Full Text] [PDF]
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S. J. Welsh, W. T. Bellamy, M. M. Briehl, and G. Powis The Redox Protein Thioredoxin-1 (Trx-1) Increases Hypoxia-inducible Factor 1{alpha} Protein Expression: Trx-1 Overexpression Results in Increased Vascular Endothelial Growth Factor Production and Enhanced Tumor Angiogenesis Cancer Res., September 1, 2002; 62(17): 5089 - 5095. [Abstract] [Full Text] [PDF]
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C. K. Sen, S. Khanna, B. M. Babior, T. K. Hunt, E. C. Ellison, and S. Roy Oxidant-induced Vascular Endothelial Growth Factor Expression in Human Keratinocytes and Cutaneous Wound Healing J. Biol. Chem., August 30, 2002; 277(36): 33284 - 33290. [Abstract] [Full Text] [PDF]
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N. Gao, M. Ding, J. Z. Zheng, Z. Zhang, S. S. Leonard, K. J. Liu, X. Shi, and B.-H. Jiang Vanadate-induced Expression of Hypoxia-inducible Factor 1alpha and Vascular Endothelial Growth Factor through Phosphatidylinositol 3-Kinase/Akt Pathway and Reactive Oxygen Species J. Biol. Chem., August 23, 2002; 277(35): 31963 - 31971. [Abstract] [Full Text] [PDF]
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|
S. F. Abcouwer, P. L. Marjon, R. K. Loper, and D. L. Vander Jagt Response of VEGF Expression to Amino Acid Deprivation and Inducers of Endoplasmic Reticulum Stress Invest. Ophthalmol. Vis. Sci., August 1, 2002; 43(8): 2791 - 2798. [Abstract] [Full Text] [PDF]
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R. H. WENGER Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression FASEB J, August 1, 2002; 16(10): 1151 - 1162. [Abstract] [Full Text] [PDF]
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|
S. J. Leibovich, J.-F. Chen, G. Pinhal-Enfield, P. C. Belem, G. Elson, A. Rosania, M. Ramanathan, C. Montesinos, M. Jacobson, M. A. Schwarzschild, et al. Synergistic Up-Regulation of Vascular Endothelial Growth Factor Expression in Murine Macrophages by Adenosine A2A Receptor Agonists and Endotoxin Am. J. Pathol., June 1, 2002; 160(6): 2231 - 2244. [Abstract] [Full Text] [PDF]
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 S. Hashimoto, N. Minami, R. Takakura, and H. Imai Bovine Immature Oocytes Acquire Developmental Competence During Meiotic Arrest In Vitro Biol Reprod, June 1, 2002; 66(6): 1696 - 1701. [Abstract] [Full Text] [PDF]
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T. Shoshani, A. Faerman, I. Mett, E. Zelin, T. Tenne, S. Gorodin, Y. Moshel, S. Elbaz, A. Budanov, A. Chajut, et al. Identification of a Novel Hypoxia-Inducible Factor 1-Responsive Gene, RTP801, Involved in Apoptosis Mol. Cell. Biol., April 1, 2002; 22(7): 2283 - 2293. [Abstract] [Full Text] [PDF]
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L. D. Ke, Y.-X. Shi, and W. K. A. Yung VEGF121, VEGF165 Overexpression Enhances Tumorigenicity in U251 MG but not in NG-1 Glioma Cells Cancer Res., March 1, 2002; 62(6): 1854 - 1861. [Abstract] [Full Text] [PDF]
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N. M. Mazure, C. Chauvet, B. Bois-Joyeux, M.-A. Bernard, H. Nacer-Cherif, and J.-L. Danan Repression of {alpha}-Fetoprotein Gene Expression under Hypoxic Conditions in Human Hepatoma Cells: Characterization of a Negative Hypoxia Response Element That Mediates Opposite Effects of Hypoxia Inducible Factor-1 and c-Myc Cancer Res., February 1, 2002; 62(4): 1158 - 1165. [Abstract] [Full Text] [PDF]
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 H. O. Akman, H. Zhang, M. A. Q. Siddiqui, W. Solomon, E. L. P. Smith, and O. A. Batuman Response to hypoxia involves transforming growth factor-beta 2 and Smad proteins in human endothelial cells Blood, December 1, 2001; 98(12): 3324 - 3331. [Abstract] [Full Text] [PDF]
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T. Sanchez-Elsner, L. M. Botella, B. Velasco, A. Corbi, L. Attisano, and C. Bernabeu Synergistic Cooperation between Hypoxia and Transforming Growth Factor-beta Pathways on Human Vascular Endothelial Growth Factor Gene Expression J. Biol. Chem., October 12, 2001; 276(42): 38527 - 38535. [Abstract] [Full Text] [PDF]
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A. Orimo, Y. Tomioka, Y. Shimizu, M. Sato, S. Oigawa, K. Kamata, Y. Nogi, S. Inoue, M. Takahashi, T. Hata, et al. Cancer-associated Myofibroblasts Possess Various Factors to Promote Endometrial Tumor Progression Clin. Cancer Res., October 1, 2001; 7(10): 3097 - 3105. [Abstract] [Full Text] [PDF]
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K. Neben, T. Moehler, G. Egerer, A. Kraemer, J. Hillengass, A. Benner, A. D. Ho, and H. Goldschmidt High Plasma Basic Fibroblast Growth Factor Concentration Is Associated with Response to Thalidomide in Progressive Multiple Myeloma Clin. Cancer Res., September 1, 2001; 7(9): 2675 - 2681. [Abstract] [Full Text] [PDF]
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D. A. Davis, A. S. Rinderknecht, J. P. Zoeteweij, Y. Aoki, E. L. Read-Connole, G. Tosato, A. Blauvelt, and R. Yarchoan Hypoxia induces lytic replication of Kaposi sarcoma-associated herpesvirus Blood, May 15, 2001; 97(10): 3244 - 3250. [Abstract] [Full Text] [PDF]
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Q. Shi, X. Le, J. L. Abbruzzese, Z. Peng, C.-N. Qian, H. Tang, Q. Xiong, B. Wang, X.-C. Li, and K. Xie Constitutive Sp1 Activity Is Essential for Differential Constitutive Expression of Vascular Endothelial Growth Factor in Human Pancreatic Adenocarcinoma Cancer Res., May 1, 2001; 61(10): 4143 - 4154. [Abstract] [Full Text]
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M. Cho, T. K. Hunt, and M. Z. Hussain Hydrogen peroxide stimulates macrophage vascular endothelial growth factor release Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2357 - H2363. [Abstract] [Full Text] [PDF]
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 N.M. Siafakas, M. Jordan, H. Wagner, E.C. Breen, H. Benoit, and P.D. Wagner Diaphragmatic angiogenic growth factor mRNA responses to increased ventilation caused by hypoxia and hypercapnia Eur. Respir. J., April 1, 2001; 17(4): 681 - 687. [Abstract] [Full Text] [PDF]
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M. WARTENBERG, F. DONMEZ, F. C. LING, H. ACKER, J. HESCHELER, and H. SAUER Tumor-induced angiogenesis studied in confrontation cultures of multicellular tumor spheroids and embryoid bodies grown from pluripotent embryonic stem cells FASEB J, April 1, 2001; 15(6): 995 - 1005. [Abstract] [Full Text] [PDF]
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 E. M. Conway, D. Collen, and P. Carmeliet Molecular mechanisms of blood vessel growth Cardiovasc Res, February 16, 2001; 49(3): 507 - 521. [Full Text] [PDF]
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K. B. Sandau, J. Fandrey, and B. Brune Accumulation of HIF-1{alpha} under the influence of nitric oxide Blood, February 15, 2001; 97(4): 1009 - 1015. [Abstract] [Full Text] [PDF]
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W. Zheng, E. A. Seftor, C. J. Meininger, M. J. C. Hendrix, and R. J. Tomanek Mechanisms of coronary angiogenesis in response to stretch: role of VEGF and TGF-{beta} Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H909 - H917. [Abstract] [Full Text] [PDF]
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C. Robinson and S. Stringer The splice variants of vascular endothelial growth factor (VEGF) and their receptors J. Cell Sci., January 3, 2001; 114(5): 853 - 865. [Abstract] [PDF]
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J. Grunstein, J. J. Masbad, R. Hickey, F. Giordano, and R. S. Johnson Isoforms of Vascular Endothelial Growth Factor Act in a Coordinate Fashion To Recruit and Expand Tumor Vasculature Mol. Cell. Biol., October 1, 2000; 20(19): 7282 - 7291. [Abstract] [Full Text]
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J. Sugawara, S. I. Tazuke, L. F-Suen, D. R. Powell, F. Kaper, A. J. Giaccia, and L. C. Giudice Regulation of Insulin-Like Growth Factor-Binding Protein 1 by Hypoxia and 3',5'-Cyclic Adenosine Monophosphate Is Additive in HepG2 Cells J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3821 - 3827. [Abstract] [Full Text]
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S. Boussat, S. Eddahibi, A. Coste, V. Fataccioli, M. Gouge, B. Housset, S. Adnot, and B. Maitre Expression and regulation of vascular endothelial growth factor in human pulmonary epithelial cells Am J Physiol Lung Cell Mol Physiol, August 1, 2000; 279(2): L371 - L378. [Abstract] [Full Text] [PDF]
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P. Koehne, C. Willam, E. Strauss, R. Schindler, K.-U. Eckardt, and C. Buhrer Lack of hypoxic stimulation of VEGF secretion from neutrophils and platelets Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H817 - H824. [Abstract] [Full Text] [PDF]
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T. P. Gavin, D. A. Spector, H. Wagner, E. C. Breen, and P. D. Wagner Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise J Appl Physiol, April 1, 2000; 88(4): 1192 - 1198. [Abstract] [Full Text] [PDF]
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 G. McMahon VEGF Receptor Signaling in Tumor Angiogenesis Oncologist, April 1, 2000; 5(90001): 3 - 10. [Abstract] [Full Text]
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 Y. Hojo, U. Ikeda, Y. Zhu, M. Okada, S. Ueno, H. Arakawa, H. Fujikawa, T.-a. Katsuki, and K. Shimada Expression of vascular endothelial growth factor in patients with acute myocardial infarction J. Am. Coll. Cardiol., March 15, 2000; 35(4): 968 - 973. [Abstract] [Full Text] [PDF]
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H. J. H. Marti, M. Bernaudin, A. Bellail, H. Schoch, M. Euler, E. Petit, and W. Risau Hypoxia-Induced Vascular Endothelial Growth Factor Expression Precedes Neovascularization after Cerebral Ischemia Am. J. Pathol., March 1, 2000; 156(3): 965 - 976. [Abstract] [Full Text] [PDF]
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 F. Jung, L. A. Palmer, N. Zhou, and R. A. Johns Hypoxic Regulation of Inducible Nitric Oxide Synthase via Hypoxia Inducible Factor-1 in Cardiac Myocytes Circ. Res., February 18, 2000; 86(3): 319 - 325. [Abstract] [Full Text] [PDF]
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J. R. Mathura Jr, N. Jafari, J. T. Chang, S. F. Hackett, K. J. Wahlin, N. G. Della, N. Okamoto, D. J. Zack, and P. A. Campochiaro Bone Morphogenetic Proteins-2 and -4: Negative Growth Regulators in Adult Retinal Pigmented Epithelium Invest. Ophthalmol. Vis. Sci., February 1, 2000; 41(2): 592 - 600. [Abstract] [Full Text]
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