Retinoic acid decreases apoptosis in mice treated with an angiogenesis inhibitor

Ju, Sun Young; Cho, Kyoung Ah; Ryu, Kyung Ha; Woo, So Youn; Park, Eun Ae; Cho, Su Jin

Abstract

OBJECTIVE
Retinoic acid is known to play a role in alveolar regeneration and is used in the prevention of bronchopulmonary dysplasia (BPD) in premature infants. Many factors involved in the pathogenesis of BPD induce apoptosis of the endothelium and epithelium of the premature lung. We hypothesized that VEGFR2 inhibition would increase apoptosis in the newborn lung and retinoic acid would decrease apoptosis in our model of inhibited lung growth.
METHODS
SU1498, a VEGFR2 inhibitor or vehicle was given to three-day-old mice. Subsequent retinoic acid or vehicle injection was given for ten days for the duration of alveolarization. Morphometric analyses were performed. Apoptosis was assessed with TUNEL staining and Annexin V staining. Co-localization of apoptotic cells with endothelial and epithelial cells was performed.
RESULTS
SU1498 injection reduced alveolar surface area and mean alveolar volume in newborn mice. Apoptosis was increased by three-fold in SU1498 injected mice. Apoptotic cells co-localized to endothelial and epithelial cells. Retinoic acid significantly reduced the degree of apoptosis by 50% in SU1498 injected mice and maintained lung development.
CONCLUSION
VEGFR2 inhibition caused an arrest in lung development accompanied by an increase in apoptosis of endothelial and epithelial cells of the neonatal lung in mice. Subsequent retinoic acid treatment reduced apoptosis and we speculate that retinoic acid may preserve lung growth in bronchopulmonary dysplasia by inhibiting apoptosis in the neonatal lung.