(Circulation. 1999;100:547-552.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Interindividual Heterogeneity in the Hypoxic Regulation of VEGF
Significance for the Development of the Coronary Artery Collateral Circulation
From the Rappaport Faculty of Medicine, Technion-Israel Institute of Technology (A.S., L.L., I.H., R.B., T.S., K.S., P.L., A.P.L.), and the Departments of Cardiology (R.B.), Medicine (A.R.), and Nephrology (K.S.), Rambam Medical Center, Haifa, Israel.
Correspondence to Dr Andrew P. Levy, Rappaport Faculty of Medicine, POB 9649, Bat Galim, Israel. E-mail alevy{at}tx.technion.ac.il
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Abstract |
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Background—The coronary artery collateral circulation may be beneficial in protecting against myocardial ischemia and necrosis. However, there is a tremendous interindividual variability in the degree of new collateral formation in patients with coronary artery disease. The basis for this interindividual heterogeneity is not understood. In this study we test the hypothesis that failure to generate collateral vessels is associated with a failure to appropriately induce with hypoxia or ischemia the angiogenic factor, vascular endothelial growth factor (VEGF).
Methods and Results—We correlated the VEGF response to hypoxia in the monocytes harvested from patients with coronary artery disease with the presence of collaterals visualized during routine angiography. We found that there was a highly significant difference in the hypoxic induction of VEGF in patients with no collaterals compared with patients with some collaterals (mean fold induction 1.9±0.2 versus 3.2±0.3, P<0.0001). After subjecting the data to ANCOVA, using as covariates a number of factors that might influence the amount of collateral formation (ie, age, sex, diabetes, smoking, hypercholesterolemia), patients with no collaterals still have a significantly lower hypoxic induction of VEGF than patients with collaterals.
Conclusions—This study provides evidence in support of the hypothesis that the ability to respond to progressive coronary artery stenosis is strongly associated with the ability to induce VEGF in response to hypoxia. The observed interindividual heterogeneity in this response may be due to environmental, epigenetic, or genetic causes. This interindividual heterogeneity may also help to explain the variable angiogenic responses seen in other conditions such as diabetic retinopathy and solid tumors.
Key Words: collateral circulation • angiogenesis • ischemia • hypoxia • growth substances
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The coronary artery collateral circulation is an anastomotic network of blood vessels that interconnects the 3 major epicardial coronary arteries. Coronary artery disease is frequently associated with a marked increase in the collateral circulation as demonstrated by angiography and autopsy studies. There now remains little doubt that the collateral circulation can be beneficial in limiting myocardial ischemia/infarction in the face of coronary artery stenosis and acute coronary occlusion.1 2 3
Although initially it was believed that all coronary collateral vessels were preformed and opened up only at times of need, it is now evident that collaterals can develop by the process of neoangiogenesis or new blood vessel formation.4 The stimulation of angiogenesis is the physiological response of a tissue to hypoxia or ischemia, which results in an increase in blood supply to the tissue.5 It was first demonstrated in tumors that there are specific growth factors that can stimulate the process of angiogenesis.6 The first such growth factor demonstrated to be hypoxia-inducible was vascular endothelial growth factor (VEGF).7 8 VEGF was subsequently demonstrated to be induced by ischemia and hypoxia in nonmalignant cells such as the cardiac myocyte and monocytes that are present in the ischemic myocardium.9 10 11 12 13 Moreover, the monocyte has recently been demonstrated to play a critical role in the angiogenic response seen in a model of chronic vascular insufficiency.14
A fundamental challenge in understanding the angiogenic response to
chronic ischemia in the clinical setting is to elucidate the
basis for interindividual differences in the degree of collateral blood
vessel formation-such that only 
50% of patients with
coronary artery stenosis develop
collaterals.3 Absence of collateral vessels in some
patients might be explained by the occurrence of acute vascular
syndromes resulting from rupture of a previously
hemodynamically insignificant atherosclerotic plaque.
However, this certainly cannot explain the marked
heterogeneity in compensatory angiogenesis observed in
many subjects with chronic stable coronary artery and
peripheral vascular disease and in hibernating
myocardium.
In the present study we test the hypothesis that failure to generate collateral vessels in many patients with chronic vascular insufficiency is associated with a failure to appropriately increase VEGF production with hypoxia or ischemia. For this purpose we have correlated the VEGF response to hypoxia in monocytes harvested from patients with coronary artery stenosis with the presence of coronary artery collaterals in the same patients. The extent of the coronary collateral circulation was determined by use of accepted criteria during routine angiography. The results revealed a highly significant correlation, with increased hypoxic induction of VEGF in those patients with collaterals in comparison to those without.
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Methods |
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Patient Recruitment
This study was approved by the Human Research Ethics Committee of the Rambam Medical Center. Informed consent was obtained from all patients. Patients were recruited consecutively from those undergoing diagnostic coronary artery catheterization at the Rambam hospital over a 3 month period. The indications for catheterization in all patients were presence of stable or unstable angina pectoris or suspected significant myocardial ischemia. Only patients with at least
1 coronary stenosis of 70% by visual
analysis of the angiogram were included in this study.
Exclusion criteria were age <18 and the presence of anemia.
Patient Data Collection
For each patient, a data sheet was completed with the patient's
name, identification number, age, sex, previous
revascularizations, history of hypertension,
diabetes, cigarette smoking, family history of premature
coronary artery disease, or
hypercholesterolemia. On a separate sheet the
patient's coronary anatomy (number of diseased vessels
and collateral score (0, 1+, 2+) was recorded by an experienced
angiographer. The collateral scoring system used was modified from the
TIMI system by grading from 0 to 2 rather than 1 to 3 but maintaining a
3 point scale.1 The ranking from 0+ to 2+ was based on the
presence of collateral vessels and opacification of the recipient
vessel. A grade of 0+ was given for no visible collaterals; 1+ for
visible collaterals but no filling of the recipient epicardial vessels;
and 2+ for filling (partial or complete) of the recipient epicardial
vessel by collaterals. A representative frame from a
patient with 2+ collaterals is shown in Figure 1
. Coronary anatomy and
collaterals were reviewed again by a cardiologist blinded to the
initial reading with a >85% concordance rate between the 2 reviewers
in the collateral score. In instances of discrepancy between the 2
reviewers, a third reviewer blinded to the readings of the first 2
reviewers was used and served as arbitrator. The coronary
anatomy and collateral score was not revealed to those involved
in the VEGF assay until after all patient samples had been
analyzed for VEGF.
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Blood Collection
Mononuclear cells were isolated from peripheral
blood by a well-established procedure initially described by
Boyum,15 performed with the use of a mixture of
polysaccharide and a radiopaque contrast medium. Forty
milliliters of blood was collected from the femoral venous catheter
placed for the catheterization before angiography was
begun. The blood was immediately placed in a 50-mL polypropylene
heparinized tube (100 µL of 5000 U/mL heparin) and kept on ice before
it was used for monocyte isolation. In all instances, the blood was
used within 4 hours of removal from the patients. Twenty milliliters of
heparinized blood was gently layered onto 10 mL of Histopaque-1077
(Sigma) in a fresh 50-mL polypropylene centrifuge tube. Tubes
were centrifuged at 1800 rpm for 30 minutes at room
temperature. Eight milliliters of plasma was removed from each tube and
saved for later use. The middle phase (buffy coat) containing the
monocytes was isolated and placed in a fresh 15-mL polypropylene
centrifuge tube. The isolated mononuclear cells were washed
twice with sterile phosphate buffered saline. The cell pellets were
resuspended in Dulbecco's modified Eagle's medium (Sigma) with 2%
fetal bovine serum (Sigma) and antibiotics. The cells were plated in 2
equal aliquots on 2 polystyrene, 10-cm-diameter tissue culture dishes
(Corning) and incubated in a 95% room air, 5%
CO2 incubator (Forma) at 37°C for 1 hour to
allow for monocyte attachment. The medium from the 2 tissue culture
dishes from a single patient was aspirated and replaced with 8 mL of
autologous plasma on each dish. One of the tissue culture dishes was
placed in a normoxic incubator, 21% O2, 5%
CO2 (Forma), and the other tissue culture dish
from the same patient was placed in a hypoxia incubator, 1%
O2, 5% CO2, 94%
N2 (Triple Gas Incubator, Jouan). After 20 hours
of exposure to either hypoxia or normoxia, RNA was extracted
from the cells.
RNA Isolation From Monocytes
Total RNA was isolated from the tissue culture dishes containing
the monocytes with the TRI Reagent (MRC Inc). Briefly, 1 mL of reagent
was added to each dish with vigorous pipetting and transferred to a 1.5
mL Eppendorf tube. Chloroform (200 µL) was added, and the tube was
vortexed and centrifuged at 14 000 rpm for 10 minutes. The RNA
was precipitated with an equal volume of isopropanol and washed with
80% ethanol. The RNA was air-dried and resuspended in water treated
with diethyl pyrocarbonate. The optical density of all of the samples
was measured at 260 nm. On average, 20 µg of RNA was obtained from
both the normoxic and hypoxic monocytes.
Measurement of the Fold Induction of VEGF mRNA by RNase
Protection Assay
The quantity of VEGF mRNA was determined by RNase protection
assay by use of a riboprobe to VEGF and to 18S rRNA to allow for sample
normalization as previously described.9
Quantification of signal intensity was performed on a
phosphorimager (Fujix). For each patient, a VEGF/18S ratio was
calculated for both the hypoxic and normoxic cells. The fold induction
of VEGF with hypoxia was calculated by dividing the hypoxic by
the normoxic value.
Statistical Analysis
Data are reported as mean±SEM. Analysis between groups
for statistically significant differences in enumerative data such as
sex, hypertension, hypercholesterolemia,
diabetes, cigarette smoking, family history, ß-blockers, or prior
coronary artery bypass grafting was performed with the use of
the 
2 test. Analysis between groups
for continuous variables such as age and number of diseased vessels
was performed with 1-way ANOVA. The fold induction of VEGF mRNA with
hypoxia was compared between patients with collateral scores of
0+, 1+, and 2+ by ANCOVA with age, number of diseased vessels, family
history of heart disease, diabetes, smoking, hypertension, prior
myocardial infarction, and hypercholesterolemia
as covariates. Bonferroni post hoc comparisons were performed to
compare the adjusted levels of VEGF between the 3 groups.
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Results |
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Patient Enrollment and Study Group Characterization
Over a 3-month period, 81 consecutive patients were approached for inclusion in this study. Six patients declined to participate. Of the remaining patients, 12 were found to have no coronary stenosis at angiography and hence were not included in the study. Twelve patients' samples were discarded for technical reasons (bacterial contamination of culture in 2 patients and inadequate amount or poor quality of extracted RNA in 10 patients). The profile of the patients with 0+, 1+, or 2+ collaterals with regard to age, sex, hypertension, hypercholesterolemia, cigarette smoking, diabetes, family history, history of prior myocardial infarction, prior coronary artery bypass grafting, ß-blocker use, and the number of diseased epicardial coronary vessels is given in the Table
. There was no statistically significant
difference between the 3 groups in any of these variables.
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Measurement of Coronary Artery Collaterals
Coronary artery collaterals were scored by visual
analysis by use of conventional criteria by the physician
performing the catheterization. All gradings were
subsequently reviewed by a single cardiologist blinded to the first
reading. There was a >85% concordance between the 2 reviewers. In
those cases in which there were disagreements between the 2 reviewers,
a third blinded reviewer was asked to review the film and served as
arbitrator. Thirty-seven percent of the patients had no collaterals,
with 25% of the patients having 1+ and 37% having 2+ collaterals.
This distribution of patients with and those without collaterals is in
agreement with previous studies in patients with obstructive
coronary disease.16
Measurement of VEGF mRNA Induction With Hypoxia
A sensitive and quantitative RNase protection analysis was
used to precisely quantify the amount of VEGF mRNA in the samples. All
values were normalized to 18S mRNA as previously
described.9 A representative RNase
protection assay demonstrating a range of differences in the hypoxic
induction of VEGF is shown in Figure 2.
There was no significant difference in the mean basal (normoxic) level
of VEGF mRNA among the 3 collateral groups. For patients with 0+
collaterals the mean normoxic VEGF/18S ratio was 0.019±0.005, for
patients with 1+ collaterals the mean normoxic VEGF/18S ratio was
0.023±0.005, and for patients with 2+ collaterals the mean normoxic
VEGF/18S ratio was 0.023±0.006. A fold induction score was determined
for each patient, comparing the ratio of VEGF/18S under hypoxia
and normoxia (Figure 3).
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Reproducibility of VEGF mRNA Induction With Hypoxia in
Monocytes
To use the fold induction of VEGF mRNA of a given patient as an
indicator of a true phenotype for that particular patient, the
values obtained must be reproducible and consistent. We
obtained blood samples on 2 or 3 different days from 5 normal
volunteers. These samples were processed in an identical fashion to
those from patients from the catheterization
laboratory. The fold inductions of VEGF mRNA with hypoxia from
different blood samples drawn on different days from the 5 different
normal volunteers were volunteer 1, 2.3, 3.1, and 4.4; volunteer
2, 1.6 and 1.7; volunteer 3, 1.0 and 1.5; volunteer 4, 1.6, 2.0, and
2.4; and volunteer 5, 5.5 and 8.1.
Statistical Analysis of Data From Patients With
Coronary Artery Disease
The unadjusted fold inductions of VEGF mRNA for coronary
artery disease patients with 0+, 1+, and 2+ collaterals were 1.9±0.2,
2.8±0.4, and 3.4±0.3, respectively. The difference in the fold
induction between patients with 0+ versus 2+ collaterals was highly
statistically significant (P<0.0001), as was the difference
in the fold induction between patients with no collaterals (0+) and
some collaterals (either 1+ or 2+) (1.9 ± 0.2 vs 3.2±0.3;
P<0.0001). In addition, there was a statistically
significant difference between the fold induction of VEGF between the
0+ and 1+ collateral groups (P<0.04). There was no
statistical difference between the fold induction of VEGF between the
1+ and 2+ collateral groups.
Data from the 3 groups with 0+, 1+, and 2+ collaterals were subjected to ANCOVA using the variables outlined above (ie, age, sex, prior myocardial infarction, hypertension, family history, hypercholesterolemia, cigarette smoking, diabetes, and number of diseased vessels) as covariates. This revealed an overall significant difference (F ratio 7.7, P<0.002). Bonferroni post hoc comparison between the groups 0+ and 1+ and between the groups 0+ and 2+ collaterals revealed a statistically significant difference in VEGF induction with hypoxia (1.5±0.4 vs 2.6±0.4, P<0.02, and 1.5±0.4 vs 3.2±0.4, P<0.0004, respectively). No significant difference was found between the groups with 1+ and 2+ collaterals (2.6±0.4 vs 3.2±0.4, P<0.3). Finally, combining groups +1 and +2 into a single group and repeating the ANCOVA for groups 0+ (no collaterals) and the combined group 1+ and 2+ (some collaterals) revealed a statistically significant difference between these 2 groups in the induction of VEGF with hypoxia (1.5±0.4 vs 2.9±0.3, P<0.003).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, we have provided evidence in support of the hypothesis that the ability to respond to progressive coronary artery stenosis by growing coronary artery collaterals is strongly associated with the ability to induce VEGF in response to hypoxia. We have shown that the presence of collaterals is correlated with a significantly higher level of induction of VEGF mRNA in monocytes derived from the same patients. Moreover, the response is graded such that the mean fold induction of VEGF is greater in patients with 2+ as compared with 1+ collaterals. Perhaps more significantly there is a highly statistically significant difference in the fold induction between the patients when divided into 2 groups: no collaterals (0+ collaterals) versus some collaterals (patients with 1+ or 2+ collaterals). This is important because although the presence of 1+ or 2+ collaterals is subject to interpretation of the catheterization films, the presence of none versus some collaterals is clear-cut. The significant difference in the induction of VEGF was maintained even after adjustment of the data for a number of variables (age, sex, prior revascularization, hypertension, hypercholesterolemia, cigarette smoking, and diabetes) that may have an affect on collateral density.17 18 19 20 21 22 None of these variables have previously been shown to have an effect on the hypoxic regulation of VEGF in monocytes. The failure to detect a role for any of these variables in terms of collateral formation in this study does not prove that they do not influence collateral formation because the power of this study may have been too small to observe such effects.
We have shown that although normoxic levels of VEGF are not significantly different between patients with different degrees of collateral vessel formation, the patients differ markedly in the hypoxic induction of VEGF mRNA. This is significant because regulation at the steady-state mRNA level is known to be of central importance in determining the VEGF response to hypoxia.8 9 The increase in VEGF mRNA in response to hypoxia is due to both an increase in the transcription of the VEGF gene and to an increase in the stability of VEGF mRNA.23 24 We have previously identified the specific trans-acting nucleic acid binding proteins, HIF-125 and HuR,26 that mediate this regulation by hypoxia.23 27 It is interesting to note that HIF-1 has recently been shown to be sensitive to posttranslational modifications that inhibit its ability to transactivate target genes.28 Further work will determine whether these or other modifications can explain the striking interindividual differences in the hypoxic induction of VEGF.
It is notable and important for future mechanistic studies that in this study we have used culture conditions in which the patient's own plasma was used to culture his or her own monocytes. Originally this was performed because the yield of monocytes and RNA was 4 to 5 times higher with the use of autologous plasma rather than a standardized commercial human plasma. It remains to be determined whether the interindividual differences we have seen in this study are due to an unidentified plasma element or due to differences in monocyte activity. The latter differences could be environmental, epigenetic, or genetic in origin. This question may be approached in future studies with monocytes from "low" and "high" VEGF responders with standardized human serum or by plasma complementation experiments. A genetic basis for this phenomenon may be identified by determining the fold induction of VEGF in monocytes of related family members. The role of a genetic component is supported not only by recent studies demonstrating that the induction of VEGF by hypoxia in multiple different human breast tumor cell lines varies widely29 but also by findings in our own laboratory that primary human foreskin fibroblasts from different donors differ markedly in their induction of VEGF with hypoxia (Levy, unpublished observations).
There are a number of immediate conceptual and clinical implications that arise from the results of this study. First, this study provides a potential explanation for the variability in collateral formation in patients with coronary artery disease. Patients identified as low VEGF responders may benefit more from treatment with parenteral recombinant VEGF to enhance collateral growth.30 31 32 Second, we have developed a simple in vitro assay to identify low and high responders that may be amenable to pharmacological intervention tailored to augment VEGF production in the low responder group. This will require identification of the precise molecular defect responsible for the lower hypoxic induction in this group. Finally, the demonstration of interindividual variability in the hypoxic induction of VEGF has implications beyond the cardiovascular system. VEGF is a key mediator of the pathological angiogenesis seen in tumors33 and in diabetic retinopathy.34 In both instances, hypoxia in the tumor or retina has been proposed to play an important role in this response. For example, it will be of interest to determine if diabetic patients who develop diabetic retinopathy are "higher inducers" of VEGF than those diabetics who do not develop retinopathy.
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Acknowledgments |
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This work was supported by the Israeli Academy of Sciences, the US-Israel Binational Science Foundation, the Israeli Cancer Research Fund, the Israeli Cancer Association, and the Rappaport Fund for Biomedical Research (all to A.P.L). The authors are grateful for the nursing assistance of Margolit Ben-Zvi and the statistical assistance of Paula Herer.
Received December 29, 1998; revision received March 24, 1999; accepted April 9, 1999.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Habib GB, Heibig J, Forman SA, Brown BG, Roberts R, Terrin ML, Bolli R. Influence of coronary artery collaterals on myocardial infarct size in humans: results of phase 1 thrombolysis in myocardial infarction (TIMI) trial. Circulation. 1991;83:739–746.
2. Hansen J. Coronary collateral circulation: clinical significance and influence on survival in patients with coronary artery occlusion. Am Heart J. 1989;117:290–295.[Medline] [Order article via Infotrieve]
3. Baroldi G. Coronary heart disease: significance of the morphologic lesions. Am Heart J. 1973;85:1–5.[Medline] [Order article via Infotrieve]
4.
Schaper W, DeBrabander M, Lewi P. DNA synthesis and
mitoses in coronary collateral vessels of the dog. Circ
Res. 1971;28:671–679.
5.
Adair TH, Gay WJ, Montani JP. Growth regulation of the
vascular system: evidence for a metabolic hypothesis.
Am J Physiol. 1990;259:R393–R404.
6. Folkman J. Tumor angiogenesis. Adv Cancer Res. 1985;43:175–203.[Medline] [Order article via Infotrieve]
7.
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara
N. Vascular endothelial growth factor is a secreted
angiogenic mitogen. Science. 1989;246:1306–1309.
8. 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]
9.
Levy A, Levy NS, Loscalzo J, Calderone A, Takahashi N,
Yeo KT, Koren G, Colucci WS, Goldberg MA. Regulation of vascular
endothelial growth factor in cardiac myocytes.
Circ Res. 1995;76:758–766.
10.
Banai S, Shweiki D, Pinson A, Chandra M, Lazarovici G,
Keshet E. Upregulation of vascular endothelial growth
factor induced by myocardial ischemia: implications for
coronary angiogenesis. Cardiovasc Res. 1994;28:1176–1179.
11.
Knighton DR, Hunt TK, Scheueenstuhl H, Halliday BJ,
Werb Z, Banda MJ. Oxygen tension regulates the expression of
angiogenesis factor by macrophages. Science. 1983;221:1283–1285.
12.
Xiong M, Elson G, Legardo D, Leibovitch SJ.
Production of vascular endothelial growth
factor by murine macrophages: regulation by hypoxia,
lactate and the inducible NO synthetase pathway. Am J
Pathol. 1998;153:587–598.
13. Harmey JH, Dimitriadis E, Kay E, Redmond HP, Bouchier-Hayes D. Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol. 1998;5:271–278.[Medline] [Order article via Infotrieve]
14. Arras M, Ito WD, Scholz D, Winkler B, Schaper J, Schaper W. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest. 1998;101:40–50.[Medline] [Order article via Infotrieve]
15. Boyum A. Separation of leukocytes from blood and bone marrow. Scand J Clin Lab Invest. 1968;21(suppl 97):77–89.
16. Ramamurthy S, Sharma S, Kumar RK, Rajani M, Wasir HS. Collateral arteries in the presence of obstructive coronary disease. Natl Med J India. 1994;7:260–262.[Medline] [Order article via Infotrieve]
17. Ilia R, Carmel S, Gueron M. Patients with coronary collaterals and normal left ventricular systolic function: clinical, hemodynamic, and angiographic characteristics. Angiology. 1998;49:631–635.
18. Kyriakides ZS, Kresmastinos DT, Michelakakis NA, Matsakas EP, Demovelis T, Toutouzas PK. Coronary collateral circulation in coronary artery disease and systemic hypertension. Am J Cardiol. 1991;67:687–690.[Medline] [Order article via Infotrieve]
19. Yarom R, Zirkin H, Stammler G, Rose AG. Human coronary microvessels in diabetes and ischaemia: morphometric study of autopsy material. J Pathol. 1992;166:265–270.[Medline] [Order article via Infotrieve]
20. Karpanou EA, Vyssoulis GP, Skoumas JN, Zervopoulos GA, Moundaki VS, Toutouzas PK. Significance of arterial hypertension on coronary collateral circulation development and left ventricular function in coronary artery disease. J Hypertens Suppl. 1988;6:S151–S153.[Medline] [Order article via Infotrieve]
21. Morimoto S, Hiasa Y, Hamai K, Wada T, Aihara T, Kataoka Y, Mori H. Influence factors on coronary collateral development. Kokyu To Junkan. 1989;37:1103–1107.[Medline] [Order article via Infotrieve]
22. Heinle RA, Levy RI, Gorlin R. Effects of factors predisposing to atherosclerosis on formation of coronary collateral vessels. Am J Cardiol. 1974;33:12–16.[Medline] [Order article via Infotrieve]
23.
Levy AP, Levy NS, Wegner S, Goldberg MA.
Transcriptional regulation of vascular endothelial
growth factor by hypoxia. J Biol Chem. 1995;270:13333–13340.
24.
Levy AP, Levy NS, Goldberg MA. Post-transcriptional
regulation of vascular endothelial growth factor by
hypoxia. J Biol Chem. 1996;271:2746–2753.
25.
Wang GL, Jiang B-H, Rue EA, Semenza GL.
Hypoxia-inducible factor 1 is a basic helix-loop-helix PAS
heterodimer regulated by cellular O2 tension.
Proc Natl Acad Sci U S A. 1995;92:5510–5514.
26.
Ma W, Cheng S, Campbell C, Wright A, Furneaux HM.
Cloning and characterization of HuR, a ubiquitously expressed elav-like
protein. J Biol Chem. 1996;271:8144–8151.
27.
Levy NS, Chang S, Furneaux HM, Levy AP. Hypoxic
stabilization of VEGF mRNA by the RNA binding protein HuR. J
Biol Chem. 1998;273:6417–6423.
28.
Sogawa K, Numayama-Tsuruta K, Ema M, Abe M, Abe H,
Fujii-Kuriyama Y. Inhibition of hypoxia-inducible factor 1
activity by nitric oxide donors in hypoxia. Proc Natl
Acad Sci U S A. 1998;95:7368–7373.
29. Scott PA, Gleadle JM, Bicknell R, Harris AL. Role of hypoxia sensing system, acidity and reproductive hormones in the variability of vascular endothelial growth factor induction in human breast carcinoma cell lines. Int J Cancer. 1998;75:706–712.[Medline] [Order article via Infotrieve]
30.
Banai S, Jaklitsch T, Shou M, Lazarous DF, Scheinowitz
M, Biro S, Epstein SE, Unger EF. Angiogenic-induced enhancement of
collateral blood flow to ischemic myocardium by
vascular endothelial growth factor in dogs.
Circulation. 1994;89:2183–2189.
31. Takeshita S, Zheng L, Brogi E, Kearney M, Pu LQ, Bunting S, Ferrara N, Symes JF, Isner JM. Therapeutic angiogenesis: a single intrarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest. 1994;93:662–670.
32.
Baumgartner I, Pieczek A, Manor O, Blair R, Kearney M,
Walsh K, Isner JM. Constitutive expression of phVEGF 165 after
intramuscular gene transfer promotes collateral development in patients
with critical limb ischemia. Circulation. 1998;97:1114–1124.
33. Plate KH, Breier HA, Weich A, Risau W. Vascular endothelial growth factor is a potential tumor angiogenesis factor in human gliomas in vivo. Nature. 1992;359:845–848.[Medline] [Order article via Infotrieve]
34.
Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD,
Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JF, Nguyen HV, Aiello
LM, Ferrara N, King G. Vascular endothelial growth
factor in ocular fluid of patients with diabetic
retinopathy and other retinal disorders. N
Engl J Med. 1994;331:1480–1487.The coronary
artery collateral circulation is beneficial in protecting against
myocardial necrosis. However, there is a tremendous interindividual
variability in the degree of new collateral formation in patients with
coronary artery disease. In this study we tested the hypothesis
that failure to generate collateral vessels is associated with a
diminished induction by hypoxia of the angiogenic factor,
vascular endothelial growth factor. We demonstrated
that there is a highly significant difference in the hypoxic induction
of vascular endothelial growth factor in patients
without coronary collaterals compared with patients with
collaterals. This interindividual heterogeneity also
may help to explain the variable angiogenic responses seen in
diabetic retinopathy and solid tumors.
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 J.-W. Lin, W. H.-H. Sheu, W.-J. Lee, Y.-T. Chen, T.-J. Liu, C.-T. Ting, and W.-L. Lee Circulating Hepatocyte Growth Factor Level but Not Basic Fibroblast Growth Factor Level Is Elevated in Angiography-Proven Symptomatic Peripheral Artery Disease Angiology, September 1, 2007; 58(4): 420 - 428. [Abstract] [PDF]
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 D. Chalothorn, J. A. Clayton, H. Zhang, D. Pomp, and J. E. Faber Collateral density, remodeling, and VEGF-A expression differ widely between mouse strains Physiol Genomics, July 18, 2007; 30(2): 179 - 191. [Abstract] [Full Text] [PDF]
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|
 T. W. Chittenden, J. A. Sherman, F. Xiong, A. E. Hall, A. A. Lanahan, J. M. Taylor, H. Duan, J. D. Pearlman, J. H. Moore, S. M. Schwartz, et al. Transcriptional Profiling in Coronary Artery Disease: Indications for Novel Markers of Coronary Collateralization Circulation, October 24, 2006; 114(17): 1811 - 1820. [Abstract] [Full Text] [PDF]
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 A. W.Y. Chung, Y. N. Hsiang, L. A. Matzke, B. M. McManus, C. van Breemen, and E. B. Okon Reduced Expression of Vascular Endothelial Growth Factor Paralleled With the Increased Angiostatin Expression Resulting From the Upregulated Activities of Matrix Metalloproteinase-2 and -9 in Human Type 2 Diabetic Arterial Vasculature Circ. Res., July 21, 2006; 99(2): 140 - 148. [Abstract] [Full Text] [PDF]
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|
 S. J. Prior, J. M. Hagberg, C. M. Paton, L. W. Douglass, M. D. Brown, J. C. McLenithan, and S. M. Roth DNA sequence variation in the promoter region of the VEGF gene impacts VEGF gene expression and maximal oxygen consumption Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1848 - H1855. [Abstract] [Full Text] [PDF]
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 K. Doi, E. Noiri, A. Nakao, T. Fujita, S. Kobayashi, and K. Tokunaga Functional Polymorphisms in the Vascular Endothelial Growth Factor Gene Are Associated with Development of End-Stage Renal Disease in Males J. Am. Soc. Nephrol., March 1, 2006; 17(3): 823 - 830. [Abstract] [Full Text] [PDF]
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 P. H Maxwell Hypoxia-inducible factor as a physiological regulator Exp Physiol, November 1, 2005; 90(6): 791 - 797. [Abstract] [Full Text] [PDF]
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M. Simons Angiogenesis: Where Do We Stand Now? Circulation, March 29, 2005; 111(12): 1556 - 1566. [Full Text] [PDF]
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Y. Cao, A. Hong, H. Schulten, and M. J. Post Update on therapeutic neovascularization Cardiovasc Res, February 15, 2005; 65(3): 639 - 648. [Abstract] [Full Text] [PDF]
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|
 A. Hoeben, B. Landuyt, M. S. Highley, H. Wildiers, A. T. Van Oosterom, and E. A. De Bruijn Vascular Endothelial Growth Factor and Angiogenesis Pharmacol. Rev., December 1, 2004; 56(4): 549 - 580. [Abstract] [Full Text] [PDF]
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 J. L. Unthank, K. M. Sheridan, and M. C. Dalsing Collateral Growth in the Peripheral Circulation: A Review Vascular and Endovascular Surgery, July 1, 2004; 38(4): 291 - 313. [Abstract] [PDF]
|
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|
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A. Roguin, J. R. Resar, J. Koerselman, Y. van der Graaf, P. P.T. de Jaegere, and D. E. Grobbee Genetics and Susceptibility of Coronary Collateral Formation * Response Circulation, November 25, 2003; 108 (21): e149 - e149. [Full Text] [PDF]
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D. J. Lenihan, A. Osman, V. Sriram, J. Aitsebaomo, and C. Patterson Evidence for association of coronary sinus levels of hepatocyte growth factor and collateralization in human coronary disease Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1507 - H1512. [Abstract] [Full Text] [PDF]
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|
|
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T. D. Bradley and J. S. Floras Sleep Apnea and Heart Failure: Part I: Obstructive Sleep Apnea Circulation, April 1, 2003; 107(12): 1671 - 1678. [Full Text] [PDF]
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 M. Nishida, T.-S. Li, K. Hirata, M. Yano, M. Matsuzaki, and K. Hamano Improvement of cardiac function by bone marrow cell implantation in a rat hypoperfusion heart model Ann. Thorac. Surg., March 1, 2003; 75(3): 768 - 773. [Abstract] [Full Text] [PDF]
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 A. Stevens, J. Soden, P. E. Brenchley, S. Ralph, and D. W. Ray Haplotype Analysis of the Polymorphic Human Vascular Endothelial Growth Factor Gene Promoter Cancer Res., February 15, 2003; 63(4): 812 - 816. [Abstract] [Full Text] [PDF]
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 L. Lavie, H. Kraiczi, A. Hefetz, H. Ghandour, A. Perelman, J. Hedner, and P. Lavie Plasma Vascular Endothelial Growth Factor in Sleep Apnea Syndrome: Effects of Nasal Continuous Positive Air Pressure Treatment Am. J. Respir. Crit. Care Med., June 15, 2002; 165(12): 1624 - 1628. [Abstract] [Full Text] [PDF]
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 J.M. Cotton, A. Mathur, Y. Hong, A.S. Brown, J.F. Martin, and J.D. Erusalimsky Acute rise of circulating vascular endothelial growth factor-A in patients with coronary artery disease following cardiothoracic surgery Eur. Heart J., June 2, 2002; 23(12): 953 - 959. [Abstract] [Full Text] [PDF]
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E. Chou, I. Suzuma, K. J. Way, D. Opland, A. C. Clermont, K. Naruse, K. Suzuma, N. L. Bowling, C. J. Vlahos, L. P. Aiello, et al. Decreased Cardiac Expression of Vascular Endothelial Growth Factor and Its Receptors in Insulin-Resistant and Diabetic States: A Possible Explanation for Impaired Collateral Formation in Cardiac Tissue Circulation, January 22, 2002; 105(3): 373 - 379. [Abstract] [Full Text] [PDF]
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R. SCHULZ, C. HUMMEL, S. HEINEMANN, W. SEEGER, and F. GRIMMINGER Serum Levels of Vascular Endothelial Growth Factor Are Elevated in Patients with Obstructive Sleep Apnea and Severe Nighttime Hypoxia Am. J. Respir. Crit. Care Med., January 1, 2002; 165(1): 67 - 70. [Abstract] [Full Text] [PDF]
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 S. B. Freedman and J. M. Isner Therapeutic Angiogenesis for Coronary Artery Disease Ann Intern Med, January 1, 2002; 136(1): 54 - 71. [Abstract] [Full Text] [PDF]
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R Tabibiazar and S.G Rockson Angiogenesis and the ischaemic heart Eur. Heart J., June 1, 2001; 22(11): 903 - 918. [PDF]
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 Y. Dor, R. Porat, and E. Keshet Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis Am J Physiol Cell Physiol, June 1, 2001; 280(6): C1367 - C1374. [Abstract] [Full Text] [PDF]
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M. Simons Therapeutic coronary angiogenesis: a fronte praecipitium a tergo lupi? Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H1923 - H1927. [Full Text] [PDF]
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M. J. Post, R. Laham, F. W. Sellke, and M. Simons Therapeutic angiogenesis in cardiology using protein formulations Cardiovasc Res, February 16, 2001; 49(3): 522 - 531. [Abstract] [Full Text] [PDF]
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M. Simons, R. O. Bonow, N. A. Chronos, D. J. Cohen, F. J. Giordano, H. K. Hammond, R. J. Laham, W. Li, M. Pike, F. W. Sellke, et al. Clinical Trials in Coronary Angiogenesis: Issues, Problems, Consensus : An Expert Panel Summary Circulation, September 12, 2000; 102 (11): e73 - e86. [Abstract] [Full Text] [PDF]
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 G. L. Semenza HIF-1 and human disease: one highly involved factor Genes & Dev., August 15, 2000; 14(16): 1983 - 1991. [Full Text]
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