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The relationship between transplacental O₂ diffusion and placental expression of PlGF, VEGF and their receptors in a placental insufficiency model of fetal growth restriction

Timothy R. H. Regnault*, Barbra de Vrijer†, Henry L. Galan‡, Meredith L. Davidsen*, Karen A. Trembler*, Frederick C. Battaglia*, Randall B. Wilkening* and Russell V. Anthony*§

Placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) are involved in placental angiogenesis through interactions with the VEGFR-1 and VEGFR-2 receptors. The placenta of pregnancies whose outcome is fetal growth restriction (FGR) are characterized by abnormal angiogenic development, classically associated with hypoxia. The present study evaluated the near-term expression of this growth factor family in an ovine model of placental insufficiency-FGR, in relationship to uteroplacental oxygenation. Compared to controls, FGR pregnancies demonstrated a 37 % increase in uterine blood flow (FGR vs. control, 610.86 ± 48.48 vs. 443.17 ± 37.39 ml min^-1 (kg fetus)^-1; P < 0.04), which was associated with an increased maternal uterine venous P_O2 (58.13 ± 1.00 vs. 52.89 ± 1.26 mmHg; P < 0.02), increased umbilical artery systolic/diastolic ratio (3.90 ± 0.33 vs. 2.12 ± 0.26, P < 0.05), and fetal hypoxia (arterial P_O2; 12.79 ± 0.97 vs. 18.65 ± 1.6 mmHg, P < 0.005). Maternal caruncle PlGF mRNA was increased in FGR (P < 0.02), while fetal cotyledon VEGF mRNA was reduced (P < 0.02). VEGFR-1 mRNA was also reduced in FGR fetal cotyledon (P < 0.001) but was not altered in caruncle tissue. Immunoblot analysis of PlGF and VEGF demonstrated single bands at 19 000 and 18 600 M_r, respectively. Caruncle PlGF concentration was increased (P < 0.04), while cotyledon VEGF was decreased (P < 0.05) in FGR placentae. The data establish that uterine blood flow is not reduced in relationship to metabolic demands in this FGR model and that the transplacental P_O2 gradient is increased, maintaining umbilical oxygen uptake per unit of tissue. Furthermore, these data suggest that an increased transplacental gradient of oxygen generates changes in angiogenic growth factors, which may underline the pathophysiology of the post-placental hypoxic FGR.

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