(Circulation. 2000;102:3098.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Ischemia-Induced Coronary Collateral Growth Is Dependent on Vascular Endothelial Growth Factor and Nitric Oxide
From the Departments of Physiology and Anesthesiology, The Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee.
Correspondence to William M. Chilian, PhD, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail chilian{at}mcw.edu
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Abstract |
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Background—We hypothesized that ischemia-induced expression of vascular endothelial growth factor (VEGF) and the production of NO stimulate coronary collateral growth.
Methods and Results—To test this hypothesis, we measured coronary collateral blood flow and VEGF expression in myocardial interstitial fluid in a canine model of repetitive myocardial ischemia under control conditions and during antagonism of NO synthase. Collateralization was induced by multiple (1/h; 8/d), brief (2 minutes) occlusions of the left anterior descending coronary artery for 21 days. In controls, collateral blood flow (microspheres) progressively increased to 89±9 mL · min-1 · 100 g-1 on day 21, which was equivalent to perfusion in the normal zone. Reactive hyperemic responses (a measure of the severity of ischemia) decreased as collateral blood flow increased. In NG-nitro-L-arginine methyl ester (L-NAME)– and L-NAME+nifedipine–treated dogs, to block the production of NO and control hypertension, respectively, collateral blood flow did not increase and reactive hyperemia was robust throughout the occlusion protocol (P<0.01 versus control). VEGF expression (Western analyses of VEGF164 in myocardial interstitial fluid) in controls peaked at day 3 of the repetitive occlusions but waned thereafter. In sham-operated dogs (instrumentation but no occlusions), expression of VEGF was low during the entire protocol. In contrast, VEGF expression was elevated throughout the 21 days of repetitive occlusions after L-NAME. Reverse transcriptase–polymerase chain reaction analyses revealed that the predominant splice variant expressed was VEGF164.
Conclusions—NO is an important regulator of coronary collateral growth, and the expression of VEGF is induced by ischemia. Furthermore, the induction of coronary collateralization by VEGF appears to require the production of NO.
Key Words: nitric oxide • collateral circulation • hyperemia • endothelium-derived factors
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Introduction |
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The coronary collateral circulation ameliorates adverse outcomes of ischemic heart disease, such as myocardial infarction, angina, and sudden death.1 2 3 Myocardial viability after acute infarction correlates with the extent of collateral blood flow of the affected vascular segment.4 Expansion of preexisting collaterals involves the addition of new vascular components (endothelium, smooth muscle, and fibroblasts) via mitosis, migration, tissue remodeling, matrix degradation, and differentiation.2 5 6 Despite the potential for coronary collateralization to abate the consequences of ischemia, there is little consensus about the signals underlying coronary collateral growth. No experiments to date have established a causal role for a particular growth factor in collateralization via receptor blockade or antagonism of downstream signaling.
Nitric oxide (NO) was suggested to stimulate hindlimb collateral growth and mediate vascular endothelial growth factor (VEGF) signaling.7 8 9 Collateral growth in the ischemic hindlimb was impaired in endothelial NO synthase (eNOS) knockout mice.9 Furthermore, the mitogenic effects of VEGF, but not those of basic fibroblast growth factor, were inhibited by antagonists of NOS.7 8 In the present study, we delineated the role of VEGF in coronary collateralization by assessing its temporal expression during collateral growth and by antagonizing the production of NO to disrupt its signaling.
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Methods |
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All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care and Use Committee of the Medical College of Wisconsin and conformed to the "Guiding Principles in the Care and Use of Animals" of the American Physiological Society and the NIH Guide for the Care and Use of Laboratory Animals.
Repetitive Coronary Occlusion Model
Mongrel dogs (either sex; 25 to 30 kg) were
anesthetized with propofol (50 mg/kg IV) and isoflurane (1.5% to
2.0%) in 100% oxygen. A left thoracotomy was performed under sterile
conditions, and the following were implanted as described
previously10 11 :
a heparin-filled catheter in the thoracic aorta for measurement of
arterial pressure; a Doppler ultrasonic flow transducer (20 MHz) on the
left anterior descending coronary artery (LAD) for measurement of
coronary blood flow velocity; a balloon cuff vascular occluder (In Vivo
Metric) around the LAD for production of brief coronary occlusions; a
heparin-filled catheter in the left atrial appendage for administration
of drugs and radioactive microspheres; and an intramyocardial catheter
(0.8-mm OD, 0.04-mm ID) in the LAD perfusion territory for sampling of
interstitial fluid. The catheter had forty 25-gauge holes punched in a
2-cm segment that was situated in the ventricular wall.
All catheters and leads were secured, tunneled subcutaneously, and exteriorized between the scapulae; the wounds were repaired, and the dog was treated postoperatively as described previously.10 11 Dogs recovered from surgery for 10 days before experimentation, and during this time period, they were trained to stand quietly in a restraining sling. Systemic and coronary hemodynamics and reactive hyperemic responses were monitored immediately before, during, and after each coronary artery occlusion.
Myocardial Interstitial Fluid
Samples of myocardial interstitial fluid (MIF) were
collected from the LAD region each morning before subsequent
experimentation. Isotonic saline (4 mL) was flushed into the catheter
as 4 mL of fluid was withdrawn. The sample was immediately placed on
ice, divided into aliquots, frozen, and stored at -80°C until
analysis. The sample "window" of the intramyocardial catheter is
0.4 mL, and the total volume of the catheter is 2.0 mL. Because
there was a 24-hour equilibration between samples, it is likely that a
significant portion of the volume within the catheter equilibrated with
MIF, so the final dilution of MIF that we analyzed is somewhere between
4- and 6-fold. We had difficulty estimating the recovery of
interstitial proteins or the equilibration time between the
interstitium and the catheter because of fibrosis. Despite these
constraints, we could measure large changes in protein concentration
within a 24-hour period, suggesting that the recovery and equilibration
times were sufficient to detect differences.
Experimental Protocols
Collateralization was induced by multiple 2-minute
occlusions of the LAD with the implanted pneumatic vascular occluder.
In 3 groups, occlusions were performed once per hour, 8 times per day,
for 21 days: (1) control (n=8): animals subjected to repetitive
occlusions; (2) NO inhibition (n=8):
NG-nitro-L-arginine
methyl ester (L-NAME, Sigma, 30 mg/kg BID), an NOS inhibitor, was
administered via the atrial catheter 2 days before initiation of
occlusions and continued throughout the 21-day protocol; and (3) NO
inhibition+nifedipine (n=4): dogs were given L-NAME according to the
same regimen as described in the preceding group in combination with
nifedipine (60 mg/d) to offset hypertension produced by inhibition of
NOS. In a sham-operated group (n=5), occlusions were not performed, and
these animals were used as time controls for analysis of VEGF in MIF.
Arterial pressure was monitored daily, and the efficacy of NO blockade
was established by measuring coronary flow and arterial pressure after
intravenous injection of acetylcholine (20, 60, and 200
ng/kg).
Regional Myocardial Blood Flow
Carbonized plastic microspheres (15±2 µm diameter,
New England Nuclear) labeled with 141Ce,
103Ru, 51Cr, or
95Nb were used to measure regional
myocardial blood flow to the normal and collateral-dependent regions at
days 0, 7, 14, and 21 of the occlusion protocol by standard
techniques.10 11
Measurements of flow were completed in only the control group and the
experimental group receiving L-NAME. We did not measure flow in the
sham group, because we have reported previously that the
instrumentation does not affect coronary collateralization, and flows
to the instrumented region were not different from that in the normal
zone.11
Western Analysis
VEGF expression in MIF was determined by Western
analysis. MIF was collected and diluted in gel loading buffer
(containing protease inhibitors, 10 mmol/L dithiothreitol, and 2%
SDS). For each sample of MIF, 400 µL initially used for
immunoprecipitation was separated in a 10% to 12% polyacrylamide gel.
After electrophoretic transfer to nylon membrane (Zeta Probe), the blot
was blocked with 5% nonfat milk in TBST (13 mmol/L Tris, pH 7.6; 150
mmol/L NaCl; 0.05% Tween 20). Mouse monoclonal VEGF primary antibody
(25 µg, Santa Cruz Biotechnology) was incubated in 1% buffered
nonfat milk for 1 hour, followed by washes and an incubation in
secondary anti-mouse IgG (Santa Cruz Biotechnology). The bands were
detected with a nonradioactive detection system (ECL from Amersham).
Molecular size standards ranging from 200 to 6.5 kDa were run
with samples to ensure quantification of the molecular size of the
signal. A 50-ng standard of human VEGF165 (R&D
systems) was also electrophoresed for comparison to the proteins in the
sample. Signals were digitized with a CCD camera-frame digitizer
system, analyzed with NIH Image software (density and band area), and
expressed as a ratio to the 50-ng standard.
Reverse Transcriptase–Polymerase Chain
Reaction
RNA was isolated from cardiac tissue by the acid
guanidinium isothiocyanate (GIT)/phenol method. Transmural samples
(500 mg) of ventricle after 21 days of repetitive occlusions were
excised and cleaned of adherent fat in ice-cold PBS. RNA was extracted,
precipitated, washed in 70% ethanol, and stored in DEPC-treated
H2O at -80°C until analysis.
Total RNA (5 µg) was reverse-transcribed with an oligo dT18 to 24 primer with Ready-To-Go You-Prime First-Strand Beads (Pharmacia Biotech) to generate first-strand cDNA (total 33 µL). We added 67 µL sterile water (total volume 100 µL) and used 2 µL of this cDNA solution for polymerase chain reaction (PCR). The resultant cDNA was amplified in 48 µL reaction buffer containing 25 pmol sense and antisense primer, 22 mmol/L Tris-HCl (pH 8.4), 55 mmol/L KCl, 1.65 mmol/L MgCl2, 220 µmol/L dGTP, 220 µmol/L dTTP, 220 µmol/L dCTP, and 22 U recombinant Taq DNA polymerase/mL. The thermal profile used a Gene Amp PCR system 2400 (Perkin-Elmer) consisting of a denaturation step of 94°C for 1 minute, an annealing step of 58°C for 1 minute, and an extension step of 72°C for 1 minute. All samples were initially denatured for a total of 5 minutes (94°C).
The sequence of VEGF sense primer was 5'-TTCTGTATC-AGTCTTTCCTGGTGAG-3', and that of antisense primer was 5'-CGAAGTGGTGAAGTTCATGGATG-3'. This primer set amplifies 4 splice variants of VEGF in dogs: VEGF121, VEGF164, VEGF182, and VEGF188.12 The PCR product for VEGF182 was undetectable; therefore, our analysis focused on VEGF121, VEGF164, and VEGF188. We cloned and sequenced PCR products to verify that the products we amplified with our VEGF primers corresponded to the known sequence of VEGF in Genbank. The PCR products of 405, 534, and 606 bp amplified by our VEGF primer corresponded to the mRNA encoding VEGF121, VEGF164, and VEGF188, respectively. The sequence of GAPDH sense primer was 5'-GCCAAAAGGGTCATCATCTC-3' and that of antisense primer was 5'-GCCCATCCACAGTCTTCT-3', which amplifies 225-bp product.
In preliminary studies, we found that the amount of PCR product increased exponentially from 26 to 36 cycles for VEGF and from 22 to 32 cycles for GAPDH. Saturation was reached after 38 and 34 cycles, respectively. Accordingly, VEGF products were amplified for 30 cycles and GAPDH products for 28 cycles. Each PCR reaction product was electrophoresed through a 2% agarose gel, and the product was visualized by incubation for 20 minutes in a solution containing 10 ng/mL ethidium bromide. Resulting gel bands were imaged with a Fluor imager (Molecular Dynamics). The relative intensities of the bands, expressed as optimal density units, were quantitatively analyzed with ImageQuaNT software (Molecular Dynamics). VEGF signals (density and band size) were normalized to the GAPDH mRNA signal, of which the latter served as internal standard.
Data Analysis
The percent debt repayment during reactive hyperemia
was calculated as (excess flow velocity during reactive hyperemia/flow
velocity debt)x100. This analysis assumes that volume flow and flow
velocities are proportional, which is probably the situation in our
experiments, because the Doppler probe was fibrosed securely in place,
and this degree of fibrosis would prevent large changes in vascular
caliber. The percent change of peak flow velocity was defined as (peak
flow velocity-basal flow velocity)/basal flow
velocityx100.
All data are expressed as mean±SEM. The changes in the parameters between the groups and over time were compared by 2-way ANOVA for repeated measurements. If significant differences were observed, then the post hoc Bonferroni-Dunn test was used to detect specific differences between the groups and across time. Differences between the L-NAME and control group reverse transcription (RT)-PCR data were analyzed with Student’s t test for unpaired observations. The level of significance was P<0.05.
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Results |
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Hemodynamic Parameters
Mean arterial pressures in controls and L-NAME+nifedipine–treated animals were similar at all times (Table 1
). In dogs treated with L-NAME, mean arterial
pressure at day 0 was significantly higher than at other time periods
and versus the other groups. Heart rates were similar in the groups
(Table 1).
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Effects of L-NAME
Acetylcholine (20 to 200 ng/kg) decreased blood
pressure and increased coronary blood flow velocity in a dose-dependent
manner. L-NAME significantly attenuated the responses to acetylcholine
(Table 2).
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Reactive Hyperemia
Figure 1 depicts myocardial reactive hyperemic responses. On
day 1, the percent increase in peak flow velocity (vasodilator reserve)
was similar in all experimental groups. The percent debt repayment was
significantly suppressed at day 1 in the L-NAME and L-NAME+nifedipine
groups compared with that of controls. Both peak flow velocity and
percent debt repayment were decreased in control experiments after
progressive repetitive occlusions, but these variables remained
unchanged in the L-NAME and L-NAME+nifedipine groups. After 21 days of
repetitive occlusions, vasodilator reserve and percent debt repayment
were significantly smaller in control than in L-NAME– and
L-NAME+nifedipine–treated dogs.
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P<0.05 vs control;
¶P<0.05 vs day
1.
Myocardial Blood Flow
In the control and L-NAME groups, myocardial blood flow
to the normal zone was unchanged at the various times, except that at
day 21 in the L-NAME group, flow was decreased compared with that at
day 0
(Table 1
). Coronary collateral blood flow in the control
group progressively increased during the repetitive occlusions. In
contrast, in L-NAME– and L-NAME+nifedipine–treated dogs, collateral
blood flow did not increase during repetitive ischemia
(Figure 2).
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Expression of VEGF Protein
VEGF protein expression peaked 3 days after initiation
of repetitive occlusions and then waned after additional coronary
occlusions in control experiments
(Figure 3). In L-NAME–treated dogs, VEGF protein was
upregulated at day 3 and remained elevated during the entire 21-day
occlusion protocol. In the sham group, VEGF levels did not change
throughout the protocol. In 2 additional animals that were treated with
the combination of L-NAME and nifedipine, VEGF analyses mimicked those
observed with L-NAME. In these animals, expression (ratio of signal
from MIF/50 ng standard) increased from baseline (0.45) to 0.86 at day
3 and remained elevated until the end of the protocol (day 21: 1.26).
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RT-PCR Analysis for VEGF mRNA
Figure 4 depicts RT-PCR for VEGF mRNA in myocardium from
ischemic (LAD perfusion area) and nonischemic (left circumflex artery
perfusion area) regions after 21 days of repetitive occlusions. The PCR
products for VEGF164 and
VEGF188 in the ischemic regions of control dogs
were at the same levels as those in the nonischemic region. In the
L-NAME group, however, the PCR products for
VEGF164 and VEGF188 in
the ischemic zone were significantly higher than those in the
nonischemic region. The PCR product for VEGF121
was barely detectable in these groups.
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Discussion |
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We have made 3 new observations: (1) expression of VEGF during coronary collateralization is time-dependent. Maximum production occurs early during repetitive ischemia and then wanes as collateral growth progresses and ischemia lessens, (2) inhibition of NOS prevents coronary collateral growth but augments expression of VEGF after repetitive episodes of myocardial ischemia, and (3) VEGF164 is the dominant splice variant of VEGF expressed during coronary collateral development. On the basis of these observations, we conclude that ischemia drives the expression of VEGF and that blockade of NO production, which reportedly interferes with the signaling of VEGF, prevents collateral growth.
Coronary Collateral Growth
Coronary collateral growth was induced by brief (2
minutes), repetitive episodes of myocardial ischemia in dogs, which is
a model that avoids myocardial stunning and tissue
necrosis.10 13 14
Repetitive episodes of myocardial ischemia in this model concomitantly
induce coronary collateral development and lead to expression of growth
factors in MIF.11
Application of MIF from animals subjected to repetitive episodes of
ischemia caused marked proliferation of endothelial and vascular smooth
muscle cells in
culture.11
Previously, we suggested that VEGF was expressed during collateral growth, because MIF-induced proliferation of cultured endothelial cells was blocked by neutralizing antibodies to VEGF at all but the earliest and latest times of collateral growth.11 There is 1 inconsistency between the present estimates of VEGF in MIF and our previous results using antibody neutralization of VEGF; specifically, we would not have expected anti-VEGF to block endothelial cell proliferation at days 12 to 13 and 19 to 20, because we predict levels of VEGF to be low at these times. We reconcile our cell culture data and the Western analyses by suggesting that during the later stages of collateral development, other growth factors are probably expressed in addition to VEGF. Blockade of 1 factor may reduce the level of all mitogens below a critical threshold value for proliferation.
Previous reports have speculated about a role for VEGF in coronary collaterals. VEGF expression is potentiated by hypoxia and is substantially increased in ischemic myocardium.15 16 17 In an ameroid model of collateral development, VEGF transcripts were elevated.16 Moreover, administration of hrVEGF or transfection of the myocardium with a plasmid or adenovirus expressing this growth factor accelerates collateral growth.18 19 This suggested that the flk and flt receptors are expressed in ischemic myocardium.20 VEGF possesses unique target cell specificity for vascular endothelial cells,15 but collateral growth involves mitosis of both endothelial and vascular smooth muscle cells.2 5 6 Other factors must exert activity in concert with VEGF. Nevertheless, our results and those of others18 19 support the concept that VEGF is an important mediator of coronary collateral growth.
Under control conditions, expression of VEGF protein in the MIF peaked early during collateral development but waned as collateral growth progressed. VEGF expression appeared to be directly related to the intensity of the ischemic signal, which was severe initially but lessened during the occlusions as collaterals developed. When collateral growth was inhibited by L-NAME and the intensity of the ischemic signal persisted during the entire occlusion protocol, VEGF expression was maintained at high levels. Taken together, these observations suggest that ischemia is the critical factor inducing expression of VEGF during coronary occlusion.
Role of NO on Coronary Collateral
Growth
Critical to our conclusions regarding the role of NO in
coronary collateralization is validation that L-NAME inhibited eNOS
activity. We have 2 observations verifying the efficacy of the
blockade. First, dilation to acetylcholine was significantly abrogated
by L-NAME. Second, the flow velocity repayment after reactive hyperemia
was significantly attenuated by L-NAME, which was previously reported,
and our results corroborate this
observation.21 22
These results attest to adequate antagonism of eNOS.
An implicit assumption we have made in our experiments and conclusions is that the effects of L-NAME are mediated by the inhibition of NOS. In addition to NO, NOS also produces superoxide,23 and L-NAME is reported to block the production of superoxide by eNOS.24 Moreover, L-NAME reportedly has some nonspecific effects, such as blockade of muscarinic receptors25 and inhibition of ornithine decarboxylase.26 Furthermore, it is possible that the hypertension produced by L-NAME affected collateral development. The increase in arterial pressure was modest, and the effects of hypertension on collateral growth are controversial.27 28 Importantly, nifedipine, an L-type calcium channel blocker, prevented hypertension but did not enable collateral growth to occur during L-NAME treatment. An alternative explanation, however, is that L-NAME produces vasoconstriction of the collateral vessels, thereby limiting collateral-dependent flow. We believe that this is unlikely, because others have not observed constriction of collateral vessels after inhibition of NOS.29 30 Despite these caveats, on the basis of our hemodynamic information and what is known about the signaling for VEGF, we believe that our results are consistent with the actions of L-NAME as an inhibitor of NO production.
The role of NO in angiogenesis and collateralization is controversial. NO inhibits migration and proliferation of vascular smooth muscle cells31 32 but promotes endothelial cell migration and tube formation.7 8 Our hypothesis that NO is critical for coronary collateral formation is corroborated by the observation that collateral formation in the peripheral circulation was impaired in eNOS-knockout mice.9 The signaling cascade activated by VEGF includes NO production,7 which explains why collateral formation is inhibited by NOS inhibition or knockout. Our results support the concept that NO is essential for the signaling of VEGF.
Clinical Implications
Abaci et
al33 recently reported that
coronary collateral development was compromised in patients with
diabetes mellitus. NO-mediated vasodilation is impaired in patients
with diabetes.34
Furthermore, Métais et
al35 suggested that
NO-mediated VEGF-induced vascular relaxation was reduced in coronary
microvessels of patients with coronary artery disease. In our
study, inhibition of NO synthesis impaired coronary collateral
development, which implies that coronary collateral growth may be
impaired in patients with deficits in NO production. Our results are
compatible with a paradigm in which collateral growth is dependent on
the production of VEGF during the initial ischemic periods and
effective endothelial production of NO to facilitate proper
signaling.
In conclusion, the expression of VEGF and production of NO are essential for growth and maturation of the coronary collateral circulation in response to myocardial ischemia.
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Acknowledgments |
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We gratefully acknowledge support from American Heart Association Fellowship Grants (Dr Matsunaga, Dr Weihrauch) and National Heart, Lung, and Blood Institute grants HL-32788 (Dr Chilian), HL-59448 (Dr Chilian), and HL-54280 (Dr Warltier).
Received April 14, 2000; revision received July 7, 2000; accepted July 14, 2000.
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H. Leong-Poi, M. A. Kuliszewski, M. Lekas, M. Sibbald, K. Teichert-Kuliszewska, A. L. Klibanov, D. J. Stewart, and J. R. Lindner Therapeutic Arteriogenesis by Ultrasound-Mediated VEGF165 Plasmid Gene Delivery to Chronically Ischemic Skeletal Muscle Circ. Res., August 3, 2007; 101(3): 295 - 303. [Abstract] [Full Text] [PDF]
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P. Rocic, C. Kolz, R. Reed, B. Potter, and W. M. Chilian Optimal reactive oxygen species concentration and p38 MAP kinase are required for coronary collateral growth Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2729 - H2736. [Abstract] [Full Text] [PDF]
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S. J. Miller, L. E. Norton, M. P. Murphy, M. C. Dalsing, and J. L. Unthank The role of the renin-angiotensin system and oxidative stress in spontaneously hypertensive rat mesenteric collateral growth impairment Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2523 - H2531. [Abstract] [Full Text] [PDF]
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J. C. Frisbee, J. B. Samora, J. Peterson, and R. Bryner Exercise training blunts microvascular rarefaction in the metabolic syndrome Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2483 - H2492. [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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F. C. Sasso, D. Torella, O. Carbonara, G. M. Ellison, M. Torella, M. Scardone, C. Marra, R. Nasti, R. Marfella, D. Cozzolino, et al. Increased Vascular Endothelial Growth Factor Expression But Impaired Vascular Endothelial Growth Factor Receptor Signaling in the Myocardium of Type 2 Diabetic Patients With Chronic Coronary Heart Disease J. Am. Coll. Cardiol., September 6, 2005; 46(5): 827 - 834. [Abstract] [Full Text] [PDF]
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T. Matsunaga, W. M. Chilian, and K. March Angiostatin is negatively associated with coronary collateral growth in patients with coronary artery disease Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2042 - H2046. [Abstract] [Full Text] [PDF]
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N. L. Lohr, D. C. Warltier, W. M. Chilian, and D. Weihrauch Haptoglobin expression and activity during coronary collateralization Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1389 - H1395. [Abstract] [Full Text] [PDF]
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P. G. Lloyd, B. M. Prior, H. Li, H. T. Yang, and R. L. Terjung VEGF receptor antagonism blocks arteriogenesis, but only partially inhibits angiogenesis, in skeletal muscle of exercise-trained rats Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H759 - H768. [Abstract] [Full Text] [PDF]
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N. Hattan, D. Warltier, W. Gu, C. Kolz, W. M. Chilian, and D. Weihrauch Autologous vascular smooth muscle cell-based myocardial gene therapy to induce coronary collateral growth Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H488 - H493. [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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G. Matsumura, S. Miyagawa-Tomita, T. Shin'oka, Y. Ikada, and H. Kurosawa First Evidence That Bone Marrow Cells Contribute to the Construction of Tissue-Engineered Vascular Autografts In Vivo Circulation, October 7, 2003; 108(14): 1729 - 1734. [Abstract] [Full Text] [PDF]
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W. Gu, D. Weihrauch, K. Tanaka, J. P. Tessmer, P. S. Pagel, J. R. Kersten, W. M. Chilian, and D. C. Warltier Reactive oxygen species are critical mediators of coronary collateral development in a canine model Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1582 - H1589. [Abstract] [Full Text] [PDF]
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J.-S. Silvestre, R. Tamarat, T. G. Ebrahimian, A. Le-Roux, M. Clergue, F. Emmanuel, M. Duriez, B. Schwartz, D. Branellec, and B. I. Levy Vascular Endothelial Growth Factor-B Promotes In Vivo Angiogenesis Circ. Res., July 25, 2003; 93(2): 114 - 123. [Abstract] [Full Text] [PDF]
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K.-i. Sasaki, J. Duan, T. Murohara, H. Ikeda, S. Shintani, T. Shimada, T. Akita, K. Egami, and T. Imaizumi Rescue of hypercholesterolemia-related impairment of angiogenesis by oral folate supplementation J. Am. Coll. Cardiol., July 16, 2003; 42(2): 364 - 372. [Abstract] [Full Text] [PDF]
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W. Schaper and D. Scholz Factors Regulating Arteriogenesis Arterioscler Thromb Vasc Biol, July 1, 2003; 23(7): 1143 - 1151. [Abstract] [Full Text] [PDF]
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T. Matsunaga, D. C. Warltier, J. Tessmer, D. Weihrauch, M. Simons, and W. M. Chilian Expression of VEGF and angiopoietins-1 and -2 during ischemia-induced coronary angiogenesis Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H352 - H358. [Abstract] [Full Text] [PDF]
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R. Koshida, J. Ou, T. Matsunaga, W. M. Chilian, K. T. Oldham, A. W. Ackerman, and K. A. Pritchard Jr Angiostatin: A Negative Regulator of Endothelial-Dependent Vasodilation Circulation, February 18, 2003; 107(6): 803 - 806. [Abstract] [Full Text] [PDF]
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J.-S. Silvestre, N. Kamsu-Kom, M. Clergue, M. Duriez, and B. I. Levy Very-Low-Dose Combination of the Angiotensin-Converting Enzyme Inhibitor Perindopril and the Diuretic Indapamide Induces an Early and Sustained Increase in Neovascularization in Rat Ischemic Legs J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 1038 - 1043. [Abstract] [Full Text] [PDF]
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X. Zhao, X. Lu, and Q. Feng Deficiency in endothelial nitric oxide synthase impairs myocardial angiogenesis Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2371 - H2378. [Abstract] [Full Text] [PDF]
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Y. Chang, B. Ceacareanu, M. Dixit, N. Sreejayan, and A. Hassid Nitric Oxide-Induced Motility in Aortic Smooth Muscle Cells: Role of Protein Tyrosine Phosphatase SHP-2 and GTP-Binding Protein Rho Circ. Res., September 6, 2002; 91(5): 390 - 397. [Abstract] [Full Text] [PDF]
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Z. S. Katusic Therapeutic Angiogenesis: New Indication for Endothelial NO Synthase Gene Transfer Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1254 - 1255. [Full Text] [PDF]
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J. L. Tuttle, T. L. Hahn, B. M. Sanders, F. A. Witzmann, S. J. Miller, M. C. Dalsing, and J. L. Unthank Impaired collateral development in mature rats Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H146 - H155. [Abstract] [Full Text] [PDF]
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J. Dulak, A. Jozkowicz, W. M. Chilian, T. Matsunaga, M. Moniz, J. Tessmer, D. Weihrauch, and D. Warltier Nitric Oxide in Vascular Endothelial Growth Factor Synthesis and Signaling Response Circulation, August 28, 2001; 104 (9): e48 - e49. [Full Text] [PDF]
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T. Matsunaga, D. W. Weihrauch, M. C. Moniz, J. Tessmer, D. C. Warltier, and W. M. Chilian Angiostatin Inhibits Coronary Angiogenesis During Impaired Production of Nitric Oxide Circulation, May 7, 2002; 105(18): 2185 - 2191. [Abstract] [Full Text] [PDF]
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