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Blood, 15 August 2001, Vol. 98, No. 4, pp. 1255-1257
BRIEF REPORT
Levels of vascular endothelial growth factor are elevated in
patients with obstructive sleep apnea-hypopnea syndrome
Shigehiko Imagawa,
Yuji Yamaguchi,
Masato Higuchi,
Tomohiro Neichi,
Yuichi Hasegawa,
Harumi Y. Mukai,
Norio Suzuki,
Masayuki Yamamoto, and
Toshiro Nagasawa
From the Division of Hematology, Institute of Clinical
Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; Center for
Sleep Respiratory Disorder at Fukuoka, Fukuoka, Japan; Chugai
Pharmaceutical Co, Ltd, Tokyo, Japan; and Center for Tsukuba Advanced
Research Alliance and Institute of Basic Medical Sciences, University
of Tsukuba, Tsukuba, Ibaraki, Japan.
 |
Abstract |
To better understand how humans adapt to hypoxia, the levels of
hemoglobin (Hb), serum erythropoietin (Epo), and vascular endothelial
growth factor (VEGF) were measured in 106 patients with severe
obstructive sleep apnea-hypopnea syndrome. The results indicated that
temporal hypoxic stimulation increases Hb. Furthermore, a minor
increase in Epo and a substantial increase in VEGF were found. The
induction in patients with severe sleep apnea was greater than that
reported in other types of hypoxia.
(Blood. 2001;98:1255-1257)
© 2001 by The American Society of Hematology.
| |
Introduction |
Remarkable progress has been made in understanding
the molecular basis of oxygen sensing and transcriptional regulation of physiologically relevant genes, including those encoding erythropoietin (Epo) and vascular endothelial growth factor (VEGF).1
Induction of these genes confers multiple responses for maintenance of
oxygen hemostasis. At the transcriptional level, these genes are all under the control of hypoxia-inducible factor-1 (HIF-1).2
There is an HIF-1 binding site in the enhancer of the Epo
gene2 and in the promoter of the VEGF
gene.3 Both of these genes are induced by hypoxia in vivo
and in vitro by means of a common oxygen and signaling
pathway.1 HIF-1 is a widely expressed heterodimeric protein composed of HIF-1 and aryl hydrocarbon nuclear translocator (ARNT) subunits, both of which belong to the rapidly growing PAS family
of basic helix-loop-helix (bHLH) transcription factors.4 At the messenger RNA (mRNA) level, both HIF-1 and
ARNT genes are constitutively expressed and not
significantly up-regulated by hypoxia. Whereas changes in oxygen
tension do not affect ARNT protein abundance, hypoxia markedly
increases the levels of HIF-1 protein.5 The
oxygen-dependent degradation (ODD) of HIF-1 is mediated by an
internal 200-residue ODD domain via the ubiquitin-proteasome pathway.6 Despite these findings in vitro, very little is
known about the steps underlying the activation of HIF-1 through the oxygen sensor by hypoxia in humans. Plasma Epo increases exponentially with the degree of hypoxia in humans.7 High altitude
stimulates Epo production in humans.8 Obstructive sleep
apnea is a recognized cause of sleep-associated
hypoxemia.9 Nocturnal oxygenation correlates with daytime
awake arterial oxygen saturation, but it cannot be accurately predicted
from awake measurements of oxygenation in patients with obstructive
sleep apnea or chronic obstructive pulmonary disease.10
Intermittent nocturnal hypoxia in patients with obstructive sleep apnea
was not accompanied by elevated serum Epo or
erythrocytosis.11 However, the number of the subjects in
this study was small (n = 26) and did not include severely affected
patients. In the present study, the responses of VEGF and Epo to
temporal hypoxic stimulation were assayed in patients with severe
obstructive sleep apnea-hypopnea syndrome (OSAHS).
| |
Study design |
We measured the levels of hemoglobin (Hb), serum VEGF, and Epo
in patients with severe OSAHS (n = 106) and compared them
with the levels in controls (n = 45). Individuals with anemia (Hb < 12.0 g/dL), renal or liver disease, and coronary artery disease were
excluded. Assays of serum VEGF and Epo were performed by enzyme-linked
immunosorbent assay. Serum samples were obtained from the patients when
they first came to the clinic. The patients, all of whom had severe
OSAHS, were divided into 5 groups according to the apnea-hypopnea index
(AHI; 30-49, 50-69, 70-89, 90-109, and > 110) and the controls had an
AHI of less than 5, as shown in Table 1.
| |
Results and discussion |
With increases in the AHI, PaO2 significantly
decreased from 89.8% ± 9.4% (in the control group) to
78.2% ± 5.1% (in the AHI > 110 group) (Figure
1). In contrast to PaO2, Hb
significantly increased from 14.5 ± 1.4 g/dL (control) to
17.2 ± 0.3 g/dL (AHI > 110 group) (Table 1). Serum VEGF
levels significantly (P < .005) increased from
150 ± 111 (control) to 755 ± 182 pg/mL (AHI > 110 group), 5 times higher than the control level (Table 1). The serum Epo level in
the control group was 10 ± 5 mU/mL (Table 1). Compared with the
control level, Epo levels in the AHI 30 to 49, 50 to 69, and 70 to 89 groups were increased to 17, 13, and 16 mU/mL, respectively
(P < .025), 1.6 times higher than the control level
(P < .025) (Table 1). However, the levels in the AHI 90 to 109 and AHI greater than 110 groups were not increased (P > .05) (Table 1). Furthermore, there were no
significant relationships between Epo and Hb, between VEGF and Hb, or
between Epo and VEGF (data not shown).
View larger version (18K):
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| Figure 1.
The level of PaO2 in patients with severe
OSAHS and controls.
* indicates P < .005; **,
P < .025.
|
|
Moore-Gillon and Cameron demonstrated that 2 hours of hypoxia (12%
oxygen) per day leads to a rise in red cell mass in rats and that there
is a dose-response relationship between the duration of hypoxia and red
cell mass.12 Other workers have shown that 1 hour of
hypoxia (10% oxygen) per day leads to a rise in hematocrit in
rats.13 However, despite substantial nocturnal hypoxemia in some patients in the former study, there was no significant effect
on serum Epo, and no significant change occurred when nocturnal hypoxemia was corrected by nasal continuous positive airway
pressure.11 Also, no patient had a serum Epo level more
than 48 mU/mL, which was the upper limit of the normal range for the
assay system used.11 Thus, intermittent nocturnal
hypoxemia in the patients was not accompanied by significantly elevated
serum Epo levels. This finding conflicted with those of Cahan and
associates,14 who demonstrated that serum Epo levels in
patients with obstructive sleep apnea were approximately 2-fold higher
than those in normal subjects. Daytime hypoxemia appears to be an
important determinant of serum Epo and red cell mass15
in patients with chronic lung disease, but nocturnal hypoxemia
does not appear to exert an appreciable independent influence on
erythrocyte production.16
We found an increase in Hb, a minor increase in Epo, and a substantial
increase in VEGF in the patients with OSAHS. The 1.6-fold increase in
Epo in our study was compatible with that in a previous report.14 This result indicates that a small increase in
Epo allows for a corresponding increase in red cell mass. The resultant enhanced delivery of oxygen to tissues then dampens the hypoxic signal,
thereby shutting off further stimulus for Epo gene
transcription. This represents the closing of a negative feedback loop.
As to the response of VEGF by hypoxia, Gunga and colleagues reported
reduced VEGF concentrations immediately after an ultramarathon run at
high altitude.17 Asano and coworkers measured a transient decrease of serum VEGF 10 days after the beginning of altitude training
at 1886 m, followed by an increase, reaching maximum values on day 19.18 Schobersberger and associates reported
that VEGF in a group of runners was significantly elevated after they ran the Swiss Alpine Marathon of Devos (distance 67 km, altitude difference 2300 m) and further increased 2.4-fold until day 5 after exposure. Epo was also increased after exercise but reached a
maximum 2 hours after the run (2-fold increase) and decreased thereafter.19 They concluded that the increase of VEGF was
due to both the stimulation of hypoxia and exercise. Especially after exercise, the tissue damage that occurred as a result of running increased the levels of cytokines such as interleukin 6 (IL-6) and
tumor necrosis factor- (TNF-) which, in turn, may have stimulated the production of VEGF mRNA.20 It is possible, though
unlikely, that changes in IL-6 and TNF- in patients with OSAHS
contribute to the observed increase in VEGF and Epo.
| |
Footnotes |
Submitted January 22, 2001; accepted April 9, 2001.
Supported by grants-in-aid for scientific research from the Ministry of
Education, Science and Culture of Japan, Renal Anemia Foundation, and
the Chugai Foundation, Tokyo, Japan.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Shigehiko Imagawa, Division of Hematology,
Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki
305-8575, Japan; e-mail: simagawa{at}md.tsukuba.ac.jp.
| |
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Abstract
Introduction