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VEGF-A, VEGFR-1, VEGFR-2 and Tie2 levels in plasma of premature infants: relationship to retinopathy of prematurity

¹ Department of Ophthalmology, University Hospital Freiburg, Freiburg, Germany
² Department of Pediatrics, University Hospital Freiburg, Freiburg, Germany
³ Department of Medical Biometry and Statistics, University of Freiburg, Freiburg, Germany
⁴ ProQinase GmbH, Clinical Biomarker Analysis, Freiburg, Germany
⁵ Department of Cancer Biology, University of Freiburg, Freiburg, Germany

Correspondence to:
Dr C Pieh, Universitäts-Augenklinik, Freiburg, Killianstrasse 5, 79106 Freiburg, Germany; christina.pieh{at}uniklinik-freiburg.de

ABSTRACT
Aim: To study prospectively the plasma levels of vascular endothelial growth factor (VEGF-A), its soluble receptors sVEGFR-1, sVEGFR-2 and soluble Tie2 in premature infants. To identify their changes related to the onset of retinopathy of prematurity (ROP).

Methods: Blood samples of 63 preterm infants born at a postmenstrual age (PMA) of 23–32 weeks were obtained between 5 days and 15 weeks after birth. 42 infants had no ROP, two had stage 1, nine stage 2 and 10 stage 3. Of these, four infants were treated with retinal photocoagulation. VEGF-A, sVEGFR-1, sVEGFR-2, and sTie2 were measured in the plasma with a sandwich enzyme immunoassay using factor-specific monoclonal mouse antibodies. The time course of concentrations plotted by kernel smoothing in infants with and without ROP were compared and a paired subgroup with analysis of variance was analysed.

Results: ROP patients had raised plasma levels of sVEGFR-2 and sTie2 compared with premature infants without ROP. VEGF-A and sVEGFR-1 levels were similar in both groups. Analysis of a subgroup with pairs of measurements, one before 32 weeks and one after 36 weeks, showed a significant increase in sTie2 after 36 weeks of PMA independent of ROP (p = 0.03).

Conclusion: This is the first study to measure plasma levels of angiogenic factors in ROP. Similar VEGF-A plasma levels in infants with and without ROP suggest that pathogenic retinal angiogenesis in ROP is mainly driven by local VEGF-A synthesis. Elevated plasma levels in active ROP were observed for sVEGFR-2 and sTie2. These increases have yet to be confirmed as predictive values for ROP.

Ethics approval: This study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of the Albert-Ludwigs-University Freiburg, Germany.