The relationship between plasma vascular endothelial growth factor and erythrocyte 2,3-bisphosphoglycerate: The putative role of chronic hypoxia

Abstract

The non-invasive assessment of chronic tissue hypoxia is difficult. Pulse oximetry only allows the peripheral oxygen saturation to be measured, while the detection of hyperlactataemia needs to take into account the fact that the accumulation of lactic acid may result from several causes other than prolonged tissue hypoxia. Arterial blood oxygen measurement is invasive and often does not give a good indication of the level of tissue hypoxia. Other suggested methods include the use of positron emission tomography, magnetic resonance T2∗ relaxation time measurement, photoacoustics and high-frequency ultrasound. Tissue hypoxia leads to increased levels of hypoxia-inducible factor-1α, which in turn upregulates VEGFA, leading to increased levels of vascular endothelial growth factor (VEGF), which promote angiogenesis. Hypoxia lasting for more than a few hours is associated with increased synthesis in erythrocytes of 2,3-bisphosphoglycerate (BPG), a powerful regulator of the allosteric properties of haemoglobin, via the Rapoport-Luebering phosphoglycerate cycle. We therefore hypothesised that plasma VEGF and erythrocyte BPG levels should be positively correlated. Venous blood samples from 34 patients (18 male, mean age (standard error) 43.4 (3.2) y) were analysed; plasma VEGF was measured using an enzyme-linked immunosorbent assay while the erythrocyte BPG was assessed by quantitative Fourier transform infrared spectrometry following gel electrophoresis. The Pearson product-moment correlation between the two variables was 0.622 (p < 0.0001). Based on our findings, we suggest that it may be useful to measure both erythrocyte BPG and plasma VEGF, together, when assessing chronic hypoxia; elevated levels of both are likely to indicate hypoxia.