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
Elevation of vascular endothelial growth factor in patients with obstructive sleep apnea–hypopnea syndrome is not due to increased platelet counts
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 (Table1-1). 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,1-1 VEGF levels increased significantly with increasing AHI.
Levels of VEGF and platelet counts with severe OSAHS and controls
| AHI . | Serum VEGF (pg/mL) . | Platelet count (× 104/μL) . | n . |
|---|---|---|---|
| Less than 5 (control) | 150 ± 111 | 24.8 ± 5.0 | 45 |
| 30-49 | 250 ± 2021-1-150 | 25.3 ± 7.2 | 41 |
| 50-69 | 582 ± 4151-1-150 | 24.4 ± 6.1 | 37 |
| 70-89 | 547 ± 5171-1-150 | 24.0 ± 4.3 | 22 |
| 90-109 | 450 ± 2501-1-150 | 25.9 ± 10.1 | 6 |
| Greater than 110 | 755 ± 1821-1-150 | 28.0 ± 5.7 | 4 |
| AHI . | Serum VEGF (pg/mL) . | Platelet count (× 104/μL) . | n . |
|---|---|---|---|
| Less than 5 (control) | 150 ± 111 | 24.8 ± 5.0 | 45 |
| 30-49 | 250 ± 2021-1-150 | 25.3 ± 7.2 | 41 |
| 50-69 | 582 ± 4151-1-150 | 24.4 ± 6.1 | 37 |
| 70-89 | 547 ± 5171-1-150 | 24.0 ± 4.3 | 22 |
| 90-109 | 450 ± 2501-1-150 | 25.9 ± 10.1 | 6 |
| Greater than 110 | 755 ± 1821-1-150 | 28.0 ± 5.7 | 4 |
P < .005 compared to AHI < 5.
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,1-2 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 disturbances1-3 and pulmonary hypertension1-4 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 α.1-5 Further studies of these latter factors are needed to clarify the response of VEGF.
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