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CORRESPONDENCE To better understand how humans adapt to hypoxia, Imagawa and
colleagues measured serum levels of vascular endothelial growth factor
in patients with sleep apnea-hypopnea syndrome. They found substantially elevated serum levels of vascular endothelial growth factor (VEGF) in those patients.1 However, what
conclusions can be drawn from this finding regarding the purpose of
their study? VEGF at higher levels in blood causes mobilization of
endothelial progenitor cells from the bone marrow and promotes
angiogenesis in vivo.2 VEGF is not only a potent inducer
of angiogenesis but also a very potent mediator of capillary leakage.
Thus, if free-circulating VEGF in the reported amounts has been present in the studied patients, one would assume clinical effects caused by
vessel leakage such as edema, weight gain, or cardiopulmonary problems. A simple explanation for the finding of elevated serum levels of VEGF
in hypoxic patients with sleep apnea-hypopnea might be thrombocytosis.
Hypoxia causes thrombocytosis,3 and virtually all of the
VEGF that is measurable in serum samples is released from platelets
during the clotting process in vitro.4,5 Unfortunately, no
blood platelet counts were reported by Imagawa and colleagues. When
plasma samples are analyzed instead of serum samples, negligible amounts of circulating VEGF can be found.6
Eberhard Gunsilius, Andreas L. Petzer, and Günther A. Gastl
References
1.
Imagawa S, Yamaguchi Y, Higuchi M, et al.
Levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea-hypopnea syndrome.
Blood.
2001;98:1255-1257
2.
Asahara T, Takahashi T, Masuda H, et al.
VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells.
EMBO J.
1999;18:3964-3972[CrossRef][Medline]
[Order article via Infotrieve].
3.
Hudson JG, Bowen AL, Navia P, et al.
The effect of high altitude on platelet counts, thrombopoietin and erythropoietin levels in young Bolivian airmen visiting the Andes.
Int J Biometeorol.
1999;43:85-90[CrossRef][Medline]
[Order article via Infotrieve].
4.
Banks RE, Forbes MA, Kinsey SE, et al.
Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology.
Br J Cancer.
1998;77:956-964[Medline]
[Order article via Infotrieve].
5.
Wartiovaara U, Salven P, Mikkola H, et al.
Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation.
Thromb Haemost.
1998;80:171-175[Medline]
[Order article via Infotrieve].
6.
Gunsilius E, Petzer A, Stockhammer G, et al.
Thrombocytes are the major source for soluble vascular endothelial growth factor in peripheral blood.
Oncology.
2000;58:169-174[CrossRef][Medline]
[Order article via Infotrieve].
Gunsilius et al raise the possibility that the elevated
vascular endothelial growth factor (VEGF) levels that we saw in our patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) may be
due to increased platelet counts that in turn lead to higher production
of VEGF during clotting. Because we did not report platelet counts of
our patients, this was a reasonable supposition. However, we can report
additional data that argue against this hypothesis (Table
1). First, the platelet counts in our
patients were normal, and second, there was no correlation between
platelet count and apnea-hypopnea index (AHI). On the other hand, as
reported in our paper,1 VEGF levels increased
significantly with increasing AHI.
Gunsilius et al wondered whether we observed edema, weight gain, or cardiopulmonary problems in our patients, which would be expected to result from chronic elevated VEGF levels. We did see edema, weight gain, and systemic hypertension in some of the patients with severe OSAHS, but there was no clear relationship between the levels of VEGF and these symptoms. However OSAHS is a temporary problem that occurs during only a portion of the day,2 and half-lives of VEGF and erythropoietin (Epo) are less than 6 hours. Therefore, a lack of correlation between VEGF levels and these symptoms is not surprising. Still, cardiac arrhythmia and conduction disturbances3 and pulmonary hypertension4 have been reported in patients with sleep apnea, but in both cases these conditions were not chronic but occurred on a daily cycle. The simple explanation for the elevated VEGF levels in patients
with OSAHS is that it is induced by hypoxia. However, induction of VEGF
may be a complex process that may involve other factors such as
interleukin-6 and tumor necrosis factor
Shigehiko Imagawa, Yuji Yamaguchi, Masato Higuchi, Tomohiro Neichi, Yuichi Hasegawa, Harumi Y Mukai, Norio Suzuki, Masayuki Yamamoto, and Toshiro Nagasawa.
References 1. Imagawa S, Yamaguchi Y, Higuchi M, et al. Levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea-hypopnea syndrome. Blood. 2001;98:1255-1257.
2.
Eckardt K-U, Boutellier U, Kurtz A, Schopen M, Koller EA, Bauer C.
Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia.
J Appl Physiol.
1989;66:1785-1788 3. Guilleminault C, Connolly SJ, Winkle RA, et al. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol. 1983;52:490-494[CrossRef][Medline] [Order article via Infotrieve]. 4. Weitzenblum E, Krieger J, Apprill M, et al. Daytime pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am Rev Respir Dis. 1988;138:345-349[Medline] [Order article via Infotrieve]. 5. Minchenko A, Bauer T, Salceda S, Caro J. Hypoxia stimulation of vascular endothelial growth factor expression in vivo and in vitro. Lab Invest. 1994;71:374-379[Medline] [Order article via Infotrieve].   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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