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Department of Medicine, University of California, San Diego, La Jolla, California 92093-0623
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ABSTRACT |
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 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Moderate ethanol
consumption demonstrates a protective effect against cardiovascular
disease and improves insulin sensitivity, possibly through
angiogenesis. We investigated whether 1) ethanol would
increase skeletal muscle growth factor gene expression and 2) the effects of ethanol on skeletal muscle growth factor
gene expression were independent of exercise-induced growth factor gene
expression. Female Wistar rats were used. Four groups (saline + rest; saline + exercise; 17 mmol/kg ethanol + rest; and 17 mmol/kg ethanol + exercise) were used to measure the growth factor
response to acute exercise and ethanol administration. Vascular
endothelial growth factor (VEGF), transforming growth
factor-
1 (TGF-1), basic fibroblast growth
factor (bFGF), Flt-1, and Flk-1 mRNA were analyzed from the left
gastrocnemius by quantitative Northern blot. Ethanol increased VEGF,
TGF-1, bFGF, and Flt-1 mRNA at rest and after acute
exercise. Ethanol increased resting Flk-1 mRNA. Ethanol increased bFGF
mRNA independently of exercise. These findings suggest that
1) ethanol can increase skeletal muscle angiogenic growth
factor gene expression and 2) the mechanisms responsible for
the ethanol-induced increases in VEGF, TGF1, and Flt-1
mRNA appear to be different from those responsible for exercise-induced
regulation. Therefore, these results provide evidence in adult rat
tissue that the protective cardiovascular effects of moderate ethanol
consumption may result in part through the increase of angiogenic
growth factors.
vascular endothelial growth factor; basic fibroblast growth factor; transforming growth factor-1; Flt-1; Flk-1
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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EXCESSIVE ALCOHOL CONSUMPTION can produce both skeletal muscle and cardiac myopathy. A characteristic feature of chronic alcohol consumption is a wasting of skeletal muscle mass that is most apparent in fast-twitch type II muscle fibers (36). Even acute alcohol intoxication can cause reversible skeletal muscle dysfunction (16). Paradoxically, evidence from epidemiological studies has demonstrated a consistent association between alcohol intake and cardiovascular disease (CVD) (1, 9, 15). Consumption of one to two drinks per day demonstrates a protective effect against CVD, whereas the consumption of three or more drinks per day is associated with an increased risk for CVD.
Insulin resistance plays an important role in the pathogenesis of a number of other disease processes, including hypertension, dyslipidemia, and CVD. Recent evidence suggests that moderate alcohol consumption is associated with greater insulin sensitivity (7, 18). Skeletal muscle is the primary tissue that controls glucose disposal, where skeletal muscle capillarization is strongly correlated with insulin sensitivity (46). Bergman and Mittleman (10) suggest that an important mechanism for the slow action of insulin in vivo may be the pathway for the transport of insulin across the capillary endothelium. Thus a reduction in skeletal muscle capillarization may contribute to insulin resistance.
Vascular endothelial growth factor (VEGF) is a highly conserved endothelial specific growth factor that promotes capillary growth and endothelial proliferation and migration predominantly through binding to the VEGF receptors, Flt-1 and Flk-1 (KDR in humans). In EA hy296 cells, a human umbilical vein endothelial-derived cell line, ethanol promotes the formation of tubelike structures resembling capillaries (29). Recent reports have suggested that the vascular protective effects of ethanol may result from increased expression of VEGF. Ethanol can increase VEGF expression in coronary artery vascular smooth muscle cells (CAVSMC) (25). Ethanol did not have a direct effect on the proliferation of either CAVSMC or human umbilical vein endothelial cells (HUVEC), but the conditioned media from CAVSMC did increase HUVEC proliferation. In chicken embryo chorioallantoic membrane (CAM), ethanol has been reported to stimulate VEGF expression and angiogenesis (25). In the gastric mucosa, ethanol increases VEGF mRNA and protein expression, whereas neutralization with an anti-VEGF antibody significantly reduced the angiogenic response to ethanol-induced injury (28).
Ethanol can also alter the expression of other growth factors,
including transforming growth factor-1
(TGF-1) and basic fibroblast growth factor (bFGF)
expression. In HepG2 cells, ethanol induces the expression of
TGF-1 (27). TGF-1 expression
is increased in macrophages harvested from ethanol-treated rats
(47). In the gastric mucosa, ethanol feeding
decreased bFGF expression (34). It has been hypothesized
that ethanol-induced inhibition of cell proliferation might result from
interference with mitogenic factors such as bFGF (31).
It is well known that exercise reduces the risk of CVD (30,
43). In skeletal muscle, endurance training results in increases in oxidative enzymes and in the number of capillaries (3, 13, 42). Our laboratory has shown that acute exercise can increase angiogenic growth factor (VEGF, TGF-1, and bFGF) mRNA in
rat skeletal muscle (20, 21, 24). In the course of
these investigations into the regulation of skeletal muscle angiogenic
growth factor expression, an unanticipated increase in VEGF expression
with the use of ethanol as a solvent for drug administration was found. In addition to an increase in VEGF mRNA expression, we questioned whether ethanol also altered VEGF receptor (Flt-1 and Flk-1) mRNA expression or the gene expression of other growth factors
(TGF-1 and bFGF), which have been shown to increase in
skeletal muscle in response to acute exercise. Therefore, the purpose
of this study was to investigate the effects of ethanol on angiogenic growth factor expression in skeletal muscle at rest and after acute
exercise. We demonstrate here that 1) VEGF,
TGF-1, bFGF, and Flt-1 mRNA are increased by ethanol at
rest and to a greater level after exercise; 2) resting Flk-1
mRNA is increased by ethanol; and 3) ethanol increases bFGF
mRNA independently of exercise.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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This study was approved by the University of California, San
Diego, Animal Subjects Committee. Female Wistar rats were used throughout the study. Mean age was 67 ± 2 (SD) days, and weight was 193 ± 11 (SD) g. All rats were first familiarized with a
rodent treadmill (Omnipacer model LC-4, Omnitech, Columbus, OH) and
taught to run at 20 m/min, 10° incline for 5 min, 48 h before
the experimental protocol. The exercise bout consisted of 1 h of
treadmill running at 20 m/min, 10° incline. At 10° inclination, the
maximal treadmill running speed sustained for 2 min during an
incremental maximal test for rats of this age, weight, sex, and strain
is 40 m/min (24). Animals were housed in their cages and
allowed standard rat food and water ad libitum before undertaking the
study. Four treatment groups were defined with six rats
(n = 6) in each group: 1) saline + rest, 2) saline + exercise, 3) 17 mmol/kg ethanol + rest, and 4) 17 mmol/kg ethanol + exercise. This
dosage of ethanol would be expected to produce a blood alcohol level of
~100 mg/dl within 20 min after administration (36).
Animals were injected intraperitoneally with either saline or ethanol
20 min before the start of rest or exercise. After completion of the
exercise bout, all animals were anesthetized with 2% halothane in
oxygen, and the left gastrocnemius muscles (both heads) were removed
and total cellular RNA was isolated. Muscle samples were removed within 20 min after the completion of exercise. Samples were stored at 
80°C until analysis.
RNA isolation and Northern analysis.
The methods used for RNA isolation from rat gastrocnemius muscles and
Northern blotting for VEGF, TGF-1, bFGF, Flt-1, and Flk-1 have been described in detail previously (20).
Briefly, total cellular RNA was isolated and separated by
electrophoresis in a 6.6% formaldehyde-1% agarose gel. Fractionated
RNA was transferred by Northern blot to Zeta probe membrane (Bio-Rad,
Hercules, CA), cross-linked to the membrane by ultraviolet irradiation
for 1 min, and stored at 4°C. The blots were then probed with
oligolabeled [
-32P]deoxycytidine triphosphate cDNA
probes for VEGF, TGF-1, bFGF, Flt-1, or Flk-1.
Prehybridization and hybridization were performed in 50% formamide,
5× sodium chloride-sodium citrate (SSC), 10× Denhardt's solution, 50 mM sodium phosphate, 1% SDS, and 250 µg/ml salmon sperm DNA at
42°C. Blots were washed with 2× SSC and 0.1% SDS at room
temperature and 0.1× SSC and 0.1% SDS at 55°C (bFGF, TGF-1, Flt-1, and Flk-1) or 65°C (VEGF). Blots were
exposed to XAR-5 X-ray film (Eastman Kodak, New Haven, CT) by use of a
Cronex Lightning Plus screen at 80°C. Autoradiographs were
quantitated by densitometry within the linear range of signals and
normalized to ribosomal 18S RNA levels.
Statistical treatment.
A two-way analysis of variance (drug × exercise level) was used
to determine differences in mRNA. After a significant F
ratio, a Bonferroni post hoc analysis was used to determine
significance between conditions. Significance was established at
P 
0.05 for all statistical sets, and data reported are
means ±SE.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The mRNA response to ethanol and exercise are shown for VEGF (Fig.
1), TGF-1 (Fig.
2), and bFGF (Fig.
3) as representative Northern blots
(Figs. 1A, 2A, and 3A) and
quantitative densitometry normalized to 18S rRNA (Figs. 1B,
2B, and 3B), respectively. Gene expression was
analyzed at rest and after a single, 1-h submaximal exercise run in the
gastrocnemius muscles from animals injected with either saline or
ethanol before rest or exercise. There were significant main effects of
both ethanol and exercise on VEGF (P = 0.002 and
P = 0.01, respectively) and TGF-1
(P = 0.0004 and P < 0.0001, respectively). There was no significant interaction between ethanol and
exercise on either VEGF (P = 0.40) or
TGF-1 (P = 0.46) mRNA. However, there
was a significant interaction of ethanol and exercise on bFGF mRNA
(P = 0.007). Post hoc analysis revealed that exercise
increased bFGF mRNA. In addition, ethanol increased bFGF mRNA
independent of exercise.
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Figure 4 shows a representative Northern
blot (A) and quantitative densitometry normalized to 18S
rRNA (B) for Flt-1 mRNA in animals injected with either
saline or ethanol examined after the single, 1-h submaximal exercise
run. Flt-1 mRNA was significantly increased both by ethanol
(P = 0.0007) and exercise (P = 0.003). There was no interaction between ethanol and exercise on Flt-1 mRNA
(P = 0.11). Figure 5
shows a representative Northern blot (A) and quantitative
densitometry normalized to 18S rRNA (B) for Flk-1 mRNA
analyzed at rest and after a single, 1-h submaximal exercise run in the
gastrocnemius muscles from animals injected either with saline or
ethanol before rest or exercise. There was a significant interaction
between ethanol and exercise on Flk-1 mRNA (P = 0.03).
Post hoc analysis revealed that ethanol significantly increased Flk-1
mRNA at rest. There were no significant differences in 18S rRNA between
conditions (range 77.9 ± 6.2 to 93.2 ± 6.1 arbitrary
units).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The principal findings of the present study are 1)
VEGF, TGF-1, and Flt-1 mRNA are increased by ethanol and
exercise, 2) resting Flk-1 mRNA is increased by ethanol, and
3) ethanol increases bFGF mRNA independently of exercise.
These results demonstrate that ethanol can increase several growth
factors believed to play a role in skeletal muscle angiogenesis,
similar to published reports of the effects of ethanol on VEGF in
CAVSMC (25) and consistent with the suggestion that
ethanol can promote cardiovascular protection. Ethanol delivery
intraperitoneally at 17 mmol/kg would be expected to produce a blood
alcohol content of ~100 mg/dl within 20 min after administration
(37). Ardies et al. (4) have shown that acute
exercise in untrained rats only modestly increases ethanol clearance.
In the United States, the legal blood alcohol concentration limit for
operating a motor vehicle is usually 100 mg/dl. Thus the dosage of
ethanol delivered in this study is well within the levels observed in
humans after moderate alcohol consumption (32, 41). We did
not observe any difference in exercise performance between the saline-
and ethanol-treated groups.
Ethanol and VEGF mRNA. Recently, Gu et al. (25) demonstrated that exposure of CAVSMC to 20 mM ethanol for 18 h can increase VEGF mRNA and protein expression, whereas exposure as short as 6 h can produce significant increases in VEGF protein. Our results demonstrate that ethanol exposure in adult rat tissue can increase VEGF mRNA after exposure of only ~1.5 h. It is well known that the gastrocnemius is a mixed fiber-type muscle. In skeletal muscle, the exercise-induced increase in VEGF mRNA is localized to the subsarcolemmal region of the gastrocnemius (12). Recently, Brutsaert et al. (14) showed that, in the gastrocnemius, VEGF mRNA expression is not different between fiber types after treadmill exercise. Whether ethanol increases VEGF gene expression in nonskeletal muscle cells or alters the quantitative production of VEGF mRNA by the different muscle fiber types has not been investigated. One possible mechanism for the large increase in VEGF mRNA after ethanol and exercise may be that ethanol works through transcription pathways independent of the exercise-induced regulation of VEGF mRNA.
In CAVSMC, ethanol not only increases VEGF expression but also the expression of hypoxia inducible factor-1 (HIF-1) mRNA (25). In exercising skeletal muscle, the results during
hypoxic exercise have been equivocal. Breen et al. (12)
demonstrated that VEGF mRNA expression was greater in hypoxia than
normoxia. Gustafson et al. (26) reported a nonsignificant
increase in VEGF mRNA during restricted blood flow exercise, whereas
Richardson et al. (39) demonstrated no difference between
exercise-induced VEGF mRNA in hypoxia and normoxia. In an attempt to
reconcile these findings, Richardson et al. proposed that there might
be some threshold intracellular myocyte PO2
below which further reductions in PO2 do not
produce further increases in VEGF mRNA. Our previous results
demonstrating a plateau in the VEGF mRNA response to exercise at
workloads above ~50% support this contention (24)
because PO2 also plateaus at ~50% of maximum
during graded exercise (38). Recent work in abstract form
suggests that HIF-1 protein levels are increased and translocated
into the nucleus and that the DNA-binding activity increased in human
skeletal muscle after exercise (2). It is not possible to
distinguish whether the regulators of VEGF mRNA are different between
the ethanol-induced increase and the exercise-induced increased.
However, we did not observe an interaction between the exercise and
drug treatments in the present results, demonstrating an additive
effect of ethanol on VEGF mRNA (Fig. 1) and suggesting that the
mechanisms responsible for the ethanol-induced increase may be
different from those responsible for the exercise-induced increase in
VEGF mRNA. In might be suggested that ethanol may increase blood
flow to skeletal muscle. However, ethanol does not increase resting
skeletal muscle blood flow or steady-state exercising blood flow,
although ethanol may transiently increase exercise-induced hyperemia
(11).
Jones et al. (28) reported that intragastric
administration of ethanol induced VEGF expression and angiogenesis in
the gastric mucosa and speculated that the increase in VEGF was the
result of gastric mucosa injury leading to microvascular damage and
ischemia. The results of the present study, in which ethanol
was administered intraperitoneally, demonstrate that ethanol can induce
VEGF gene expression in tissue that is not directly exposed to ethanol
during administration and thus absent of direct tissue injury, as
previously demonstrated by Gu et al. (25). Jones and
colleagues (29) demonstrated that both protein kinase C
(PKC) and mitogen-activated protein kinase (MAPK) were increased in the
gastric mucosa after intragastric ethanol administration
(29). In skeletal muscle, exercise or electrical
stimulation activates the PKC (40) and MAPK
(5) systems. There are no known reports demonstrating that
ethanol activates either the MAPK or PKC systems in skeletal muscle.
Ethanol, TGF-1, and bFGF.
Consistent with previous reports when samples were collected
immediately after the completion of exercise (12, 24), we observed an increase in both TGF-1 and bFGF mRNA in
skeletal muscle in response to exercise. Ethanol can also alter the
expression of TGF-1 and bFGF expression (27, 33,
47). In rat skeletal muscle, ethanol increased
TGF-1 mRNA (Fig. 2). Similar to the VEGF mRNA response
in skeletal muscle, both hypoxia and exercise increase
TGF-1 mRNA (12), with a plateau in
TGF-1 mRNA in response to exercise intensities of 50%
and greater (24). Thus the greater exercise-induced
increase in TGF-1 mRNA with ethanol suggests that the
mechanisms responsible for the ethanol-induced increase may be
different from those responsible for the exercise-induced increase.
Whether HIF-1 or some other regulator is responsible for the
ethanol-induced increase in TGF-1 mRNA remains to be elucidated.
Ethanol and VEGF receptor mRNA. To our knowledge, this is the first report to demonstrate that ethanol not only increases VEGF gene expression but also upregulates the expression of both VEGF receptors. Ethanol increases NO release and endothelial NO synthase expression in endothelial cells (48). NO synthase inhibition attenuates the exercise-induced increase in skeletal muscle Flt-1 mRNA (20). Thus the increase in Flt-1 with ethanol administration may result from increased NO production. This hypothesis remains to be investigated.
Ethanol also increased Flk-1 mRNA at rest. Our laboratory has previously demonstrated that Flk-1 mRNA expression is unaltered acutely after exercise (20, 23), whereas Olfert et al. (35) demonstrated that immediately after acute exercise Flk-1 mRNA can be reduced. We recently demonstrated that exercise can increase skeletal muscle Flk-1 expression between 4 and 16 h after the completion of exercise (23). The mechanisms responsible for this increase remain unknown. A reduction in circulating angiotensin II, via captopril, reduces Flk-1 mRNA independent of exercise (20). Recent work suggests that ethanol potentiates angiotensin II induced activation of MAPK (49), whereas MAPK inhibition has been shown to reduce ligand-induced expression of Flk-1 (45). Whether angiotensin II or MAPK is involved in the ethanol-induced increase in Flk-1 gene expression remains to be elucidated. The biological activity of VEGF is produced through ligand binding to the VEGF receptors, Flt-1 and Flk-1. Homozygous mutation of either VEGF receptor gene in mice results in embryonic lethality, as a result of profound deficits in vasculogenesis. Flt-1 is crucial in the organization of the developing vasculature, whereas Flk-1 is essential for embryonic endothelial cell differentiation and vasculogenesis (19, 44). These high-affinity VEGF receptors are localized predominantly to the vascular endothelium, not only on proliferating endothelial cells but also on quiescent cells as well (17). A prerequisite for tumor angiogenesis is tumor expression of VEGF, as well as expression of Flt-1 and Flk-1 (6). Thus the coexpression of mRNA for VEGF and the VEGF receptors by ethanol is consistent with the coordinate action of VEGF. In summary, we have demonstrated that 1) ethanol increases VEGF, TGF-1, bFGF, and Flt-1 mRNA at rest and during
exercise; 2) ethanol increases resting Flk-1 mRNA; and
3) ethanol increases bFGF mRNA independently of exercise.
These results provide evidence in adult rat tissue that the protective
cardiovascular effects of moderate ethanol consumption may result in
part through the increase of angiogenic growth factor expression.
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ACKNOWLEDGEMENTS |
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This study was supported by National Heart, Lung, and Blood Institute Grant HL-17731. T. P. Gavin was supported by State of California Tobacco Related Disease Research Program Grant 8KT-0081 during the preparation of this manuscript.
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. P. Gavin, 371 Ward Sports Medicine Bldg., East Carolina University, Greenville, NC 27858 (E-mail: gavint{at}mail.ecu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/japplphysiol.00929.2001
Received 6 September 2001; accepted in final form 13 November 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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|---|
1.
Ajani, UA,
Gaziano JM,
Lotufo PA,
Liu S,
Hennekens CH,
Buring JE,
and
Manson JE.
Alcohol consumption and risk of coronary heart disease by diabetes status.
Circulation
102:
500-505,
2000
2.
Ameln, HTG,
Jansson E,
Poellinger L,
Sundberg CJ,
and
Makino Y.
Activation of hypoxia inducible factor 1 in exercising human skeletal muscle (Abstract).
FASEB J
15:
A763,
2001.
3.
Andersen, P,
and
Henriksson J.
Capillary supply of the quadriceps femoris muscle of man: adaptive response to exercise.
J Physiol (Lond)
270:
677-690,
1977
4.
Ardies, CM,
Morris GS,
Erickson CK,
and
Farrar RP.
Both acute and chronic exercise enhance in vivo ethanol clearance in rats.
J Appl Physiol
66:
555-560,
1989
5.
Aronson, D,
Violan MA,
Dufresne SD,
Zangen D,
Fielding RA,
and
Goodyear LJ.
Exercise stimulates the mitogen-activated protein kinase pathway in human skeletal muscle.
J Clin Invest
99:
1251-1257,
1997[ISI][Medline].
6.
Barleon, B,
Siemeister G,
Martiny-Baron G,
Weindel K,
Herzog C,
and
Marme D.
Vascular endothelial growth factor up-regulates its receptor fms-like tyrosine kinase 1, Flt-1, and a soluble variant of Flt-1 in human vascular endothelial cells.
Cancer Res
57:
5421-5425,
1997
7.
Bell, RA,
Mayer-Davis EJ,
Martin MA,
D'Agostino RB, Jr,
and
Haffner SM
Associations between alcohol consumption and insulin sensitivity and cardiovascular disease risk factors: the Insulin Resistance and Atherosclerosis Study.
Diabetes Care
23:
1630-1636,
2000
8.
Benoit, H,
Jordan M,
Wagner H,
and
Wagner PD.
Effect of NO, vasodilator prostaglandins, and adenosine on skeletal muscle angiogenic growth factor gene expression.
J Appl Physiol
86:
1513-1518,
1999
9.
Berger, K,
Ajani UA,
Kase CS,
Gaziano JM,
Buring JE,
Glynn RJ,
and
Hennekens CH.
Light-to-moderate alcohol consumption and risk of stroke among U.S. male physicians.
N Engl J Med
341:
1557-1564,
1999
10.
Bergman, RN,
and
Mittleman SD.
Central role of the adipocyte in insulin resistance.
J Basic Clin Physiol Pharmacol
9:
205-221,
1998[Medline].
11.
Blanchley, JD,
Ferguson ER,
Long JT,
and
Knochel JP.
Normal resting and exercising muscle blood flow during acute ethanol infusion.
Clin Toxicol
17:
413-419,
1980[Medline].
12.
Breen, EC,
Johnson EC,
Wagner H,
Tseng HM,
Sung LA,
and
Wagner PD.
Angiogenic growth factor mRNA responses in muscle to a single bout of exercise.
J Appl Physiol
81:
355-361,
1996
13.
Brodal, P,
Ingjer F,
and
Hermansen L.
Capillary supply of skeletal muscle fibers in untrained and endurance-trained men.
Am J Physiol Heart Circ Physiol
232:
H705-H712,
1977
14.
Brutsaert, TD,
Breen EC,
Fu Z,
Tang K,
Agey P,
Mathieu-Costello O,
and
Wagner PD.
Fiber type specific expression of VEGF mRNA in rat gastrocnemius following 1 hour of exercise (Abstract).
FASEB J
13:
A1052,
2001.
15.
Criqui, MH.
Do known cardiovascular risk factors mediate the effect of alcohol on cardiovascular disease?
Novartis Found Symp
216:
159-172,
1998[Medline].
16.
Eichner, ER.
Ergolytic drugs in medicine and sports.
Am J Med
94:
205-211,
1993[ISI][Medline].
17.
Ferrara, N.
Molecular and biological properties of vascular endothelial growth factor.
J Mol Med
77:
527-543,
1999[ISI][Medline].
18.
Flanagan, DEH,
Moore VM,
Godsland IF,
Cockington RA,
Robinson JS,
and
Phillips DI.
Alcohol consumption and insulin resistance in young adults.
Eur J Clin Invest
30:
297-301,
2000[ISI][Medline].
19.
Fong, GH,
Rossant J,
Gerenstein M,
and
Breitman M.
Role of Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium.
Nature
376:
66-67,
1995[Medline].
20.
Gavin, TP,
Spector DA,
Wagner H,
Breen EC,
and
Wagner PD.
Effect of captopril on skeletal muscle angiogenic growth factor responses to exercise.
J Appl Physiol
88:
1690-1697,
2000
21.
Gavin, TP,
Spector DA,
Wagner H,
Breen EC,
and
Wagner PD.
Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise.
J Appl Physiol
88:
1192-1198,
2000
22.
Gavin, TP,
Wagner H,
and
Wagner PD.
VEGF receptor (Flt-1) mRNA and nitric oxide synthase inhibition (Abstract).
FASEB J
14:
A324,
2001.
23.
Gavin, TP,
and
Wagner PD.
VEGF receptor (Flt-1) mRNA response to acute exercise (Abstract).
Med Sci Sports Exerc
32:
S103,
2000.
24.
Gavin, TP,
and
Wagner PD.
Effect of short-term exercise training on angiogenic growth factor gene responses in rats.
J Appl Physiol
90:
1219-1226,
2001
25.
Gu, JW,
Elam J,
Sartin A,
Li W,
Roach R,
and
Adair TH.
Moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate angiogenesis.
Am J Physiol Regulatory Integrative Comp Physiol
281:
R365-R372,
2001
26.
Gustafsson, T,
Puntschart A,
Kaijser L,
Jansson E,
and
Sundberg CJ.
Exercise-induced expression of angiogenesis-related transcription and growth factors in human skeletal muscle.
Am J Physiol Heart Circ Physiol
276:
H679-H685,
1999
27.
Gutierrez-Ruis, MC,
Quiroz SC,
Souza V,
Bucio L,
Hernandez E,
Olivares IP,
Llorente L,
Vargas-Vorackova F,
and
Kershenobich D.
Cytokines, growth factors, and oxidative stress in HepG2 cells treated with ethanol, acetaldehyde, and LPS.
Toxicology
134:
197-207,
1999[ISI][Medline].
28.
Jones, MK,
Itano RM,
Wang H,
Tomikawa M,
Sarfeh IJ,
Szabo S,
and
Tarnawski AS.
Activation of VEGF and Ras genes in gastric mucosa during angiogenic response to ethanol injury.
Am J Physiol Gastrointest Liver Physiol
276:
G1345-G1355,
1999
29.
Jones, MK,
Sarfeh IJ,
and
Tarnawski AS.
Induction of in vitro angiogenesis in the endothelial-derived cell line EA hy296, by ethanol is mediated though PKC and MAPK.
Biochem Biophys Res Commun
249:
118-123,
1998[ISI][Medline].
30.
Lee, IM,
Sesso HD,
and
Paffenbarger RS, Jr.
Physical activity and coronary heart disease risk in men: does the duration of exercise episodes predict risk?
Circulation
102:
981-986,
2000
31.
Luo, J,
and
Miller MW.
Growth factor-mediated neural proliferation: target of ethanol toxicity.
Brain Res Rev
27:
157-167,
1998[Medline].
32.
Modell, JG,
and
Mountz JM.
Drinking and flying
the problem of alcohol use by pilots.
N Engl J Med
323:
455-461,
1990[ISI][Medline].
33.
Nakamura, M,
Akiba Y,
Kishikawa H,
Oda M,
and
Ishii H.
Effect of combined administration of lansoprazole and sofalcone on microvascular and connective tissue regeneration after ethanol-induced gastrci muscosal damage.
J Clin Gastroenterol
27, Suppl1:
S170-S177,
1998.
34.
Nakamura, M,
Akiba Y,
Oda M,
and
Ishii H.
Alteration of basic fibroblast growth factor concentration and immunoreactivity in healing of ethanol-induced gastric mucosal damage: effect of sofalcone.
J Clin Gastroenterol
25, Suppl1:
S13-S20,
1997.
35.
Olfert, IM,
Breen C,
Mathieu-Costello O,
and
Wagner PD.
Chronic hypoxia attenuates resting and exercise-induced VEGF, Flt-1, and Flk-1 mRNA levels in skeletal muscle.
J Appl Physiol
90:
1532-1538,
2001
36.
Preedy, VR,
Salisbury JR,
and
Peters TJ.
Alcoholic muscle disease: features and mechanisms.
J Pathol
173:
309-315,
1994[ISI][Medline].
37.
Reilly, ME,
Mantle D,
Richardson PJ,
Salisbury J,
Jones J,
Peters TJ,
and
Preedy VR.
Studies on the time-course of ethanol's acute effects on skeletal muscle protein synthesis: comparisom with acute changes in proteolytc activity.
Alcohol Clin Exp Res
21:
792-798,
1997[ISI][Medline].
38.
Richardson, RS,
Noyszewski EA,
Kendrick KF,
Leigh JS,
and
Wagner PD.
Myoglobin O2 desaturation during exercise: evidence of limited O2 transport.
J Clin Invest
96:
1916-1926,
1995.
39.
Richardson, RS,
Wagner H,
Mudaliar SRD,
Henry R,
Noyszewski EA,
and
Wagner PD.
Human VEGF gene expression in skeletal muscle: effect of acute normoxic and hypoxic exercise.
Am J Physiol Heart Circ Physiol
277:
H2247-H2252,
1999
40.
Richter, EA,
Cleland PJ,
Rattigan S,
and
Clark MG.
Contraction-associated translocation of protein kinase C in rat skeletal muscle.
FEBS Lett
217:
232-236,
1987[ISI][Medline].
41.
Ritchie, JM.
The alipathic alcohols.
In: Pharmacological Basis of Therapeutics (4th ed.). New York: Macmillan, 1971, p. 135-150.
42.
Robinson, DM,
Ogilvie RW,
Tullson PC,
and
Terjung RL.
Increased peak oxygen consumption of trained muscle requires increased electron flux capacity.
J Appl Physiol
77:
1941-1952,
1994
43.
Sesso, HD,
Paffenbarger RS, Jr,
and
Lee IM.
Physical activity and coronary heart disease in men: the Harvard Alumni Health Study.
Circulation
102:
975-980,
2000
44.
Shalaby, F,
Roussant J,
Yamaguchi TP,
Gerenstein M, XF,
Wu Breitman ML,
and
Schuh AC.
Failure of blood island formation and vasculogenesis in Flk-1 deficient mice.
Nature
376:
62-66,
1995[Medline].
45.
Shen, BQ,
Lee DY,
Gerber HP,
Keyt BA,
Ferrara N,
and
Zioncheck TF.
Homologous up-regulation of KDR/Flk-1 receptor expression by vascular endothelial growth in vitro.
J Biol Chem
273:
29979-29985,
1998
46.
Shono, N,
Mizuno M,
Nishida H,
Higaki Y,
Urata H,
Tanaka H,
Quistorff B,
Saltin B,
Shindo M,
and
Nishizumi M.
Decreased skeletal muscle capillary density is related to higher serum levels of low-density lipoprotein cholesterol and apolipoprotein B in men.
Metabolism
48:
1267-1271,
1999[Medline].
47.
Singhal, PC,
Reddy K,
Ding G,
Kapasi A,
Franki N,
Ranjan R,
Nwakoby IE,
and
Gibbons N.
Ethanol-induced marcophage apoptosis: the role of TGF-.
J Immunol
162:
3031-3036,
1999
48.
Venkov, CD,
Myers PR,
Tanner MA,
Su M,
and
Vaughan DE.
Ethanol increases endothelial nitric oxide production through modulation of nitric oxide synthase expression.
Thromb Haemost
81:
638-642,
1999[ISI][Medline].
49.
Weng, Y,
and
Shukla DS.
Ethanol alters angiotensin II stimulated mitogen activated protein kinase in hepatocytes: agonist selectivity and ethanol metabolic independence.
Eur J Pharmacol
398:
323-331,
2000[ISI][Medline].
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