Gender-related effects of prenatal administration of estrogen and progesterone receptor antagonists on VEGF and surfactant-proteins and on alveolarisation in the developing piglet lung

Abstract

Background: Vascular endothelial growth factor (VEGF) is essential for embryonic lung development and has been shown to be regulated by estradiol (E2) and progesterone (P).

Aim: To investigate the effects of prenatal E2 and P withdrawal by specific receptor antagonists on the mRNA expression of VEGF, surfactant proteins (SP-B and SP-C) and on alveolarisation in lung tissue of male and female pig fetuses.

Methods: Fetuses from 10 sows were randomized to receive either both an intramuscular injection of the E2 receptor blocker ICI 182.780 and the P receptor blocker RTI 3021-022 (ICI+RTI, n=5) or a placebo injection (n=5) at 90 days of gestation (DOG, 115=term). After delivery by cesarean section on 114 DOG, tissue of the left lingula of the piglet's lung (28 placebo, 26 ICI+RTI) was obtained to determine the mRNA expression of VEGF, SP-B and SP-C. Lungs from 15 placebo and 14 ICI+RTI group piglets were removed and alveolar counts performed.

Results: The ICI+RTI group showed significantly lower SP-C mRNA expression and alveolar counts compared to the placebo group (p=0.04 and 0.03, respectively). Diminished alveolarisation in the ICI+RTI group was mainly due to the reduction of alveolar counts in male piglets (p=0.02). Within the placebo group VEGF and SP-B mRNA expression in male piglets were significantly lower compared to female piglets (p=0.01 and 0.004, respectively). ICI+RTI treatment abolished this gender-related difference.

Conclusion: Estradiol and P antagonism affected gender-related differences of key proteins for pulmonary function and development and especially in males was associated with diminished alveolarisation.