Acute hypoxia decreases plasma VEGF concentration in healthy humans

Abstract

Vascular endothelial growth factor (VEGF) is known to be upregulated by hypoxia in vitro. However, in vivo data about VEGF regulation in chronic hypoxic diseases are conflicting. We investigated the effects of hypoxia on plasma VEGF concentration in healthy subjects. To control known confounders, such as insulin, glucose concentrations, or exercise, hypoxic effects on VEGF were studied during experimentally clamping glucose concentrations at rest. In a double-blind crossover study design, we induced hypoxia for 30 min by decreasing oxygen saturation to 75% (vs. normoxic control) in 14 healthy men. Plasma VEGF concentration was determined at baseline, immediately after hypoxia had ended, and after a further 150 min. Levels of its soluble (s)Flt-1 receptor were assessed at baseline and at the end of the clamp. In parallel, catecholamine and cortisol levels were monitored. To investigate potential effects of glucose administration on the release of VEGF, we performed a third session, reducing glucose infusion for 30 min while serum insulin was held stable thereby inducing hypoglycemia. Hypoxia decreased VEGF levels compared with the normoxic control ( P < 0.05). VEGF concentrations increased during hypoglycemia ( P < 0.02) but were comparable to the normoglycemic control at the end of the clamp ( P > 0.80). sFlt-1 receptor concentration remained unchanged during hypoxia and hypoglycemia compared with control (both P > 0.4). Epinephrine concentration ( P < 0.01) increased upon hypoxia, whereas norepinephrine and cortisol did not change. Contrary to in vitro studies, in healthy humans hypoxia decreases plasma VEGF concentration, suggesting that systemic VEGF concentration may be differently regulated than the expression on cellular basis.

Divergent effects of hyper- and hypoglycemia on circulating vascular endothelial growth factor in humans

“…Results from the hypoglycemic intervention are consistent with previous investigations demonstrating an increase of circulating VEGF concentrations upon blood glucose drop in humans [11][12][13], although data from the present study failed to reach significance probably because of the short period of blood sampling after induction of hypoglycemia. In contrast, brief hyperglycemia clearly decreases circulating VEGF concentrations.…”

“…Although it was previously found in accordance with in vitro data that hypoglycemia induces a rapid increase in circulating VEGF concentrations in humans [11][12][13], our group could also demonstrate that, contrasting to in vitro investigations, acute hypoxia decreases plasma VEGF concentrations in healthy men [13]. It has been postulated that high glucose concentrations induce a pseudohypoxic state because of a high NADH + /NAD + ratio in cells even when the oxygen tension is normal [14].…”

“…Subsequently, blood glucose was normalized again by infusion of a 20% dextrose solution or by physiological glucose degradation. Hormone probes were sampled and measurements were performed as previously described [13].…”

Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans

“…Furthermore, the effect of the length of the training and the length of propensity for altered responses after training has yet to be determined. However, the effects on epinephrine are likely a consequence of both the hyperventilation phase and hypoxia due to breath retention, as both have been demonstrated to increase epinephrine levels (18,(21)(22)(23)(24). The hyperventilation-induced increase in epinephrine was shown to be dependent on decreased levels of bicarbonate, as hyperventilation combined with bicarbonate infusion (resulting in hypocapnia and alkalosis, but normal bicarbonate levels) nullified epinephrine increase (24).…”

Effects of hydralazine on the pulmonary vasculature and respiratory control in humans

“…However, for VEGF this is not necessarily the case. While there is clear evidence in cell culture to show that hypoxia induces an increase in the expression of VEGF (Ferrara, 2004), nevertheless Oltmanns et al (2006) found that acute systemic hypoxia may decrease circulating VEGF levels. Furthermore, a recent study has demonstrated that substantial temporal dissociation between mRNA and protein levels may occur for VEGF in the skeletal muscle of rats (Milkiewicz et al 2006).…”