Fetal pulmonary vascular remodeling in a rat model induced by hypoxia and indomethacin

Abstract

Objective. This study sought to determine the effect of combined treatment of hypoxia plus indomethacin on pulmonary vascular remodeling in fetal rats.

Methods. Hypoxia and indomethacin were used to treat pregnant rats during 19–21 days of gestation. The adventitia, media, and intima of pulmonary arteries from fetal rats were assessed. Western blots were used for determining the abundance of smooth muscle specific alpha-actin protein (α-SMA), elastin, and endothelial nitric oxide synthase (eNOS) in lung tissues. Plasma brain-type natriuretic peptide (BNP) levels, reflecting the increased right ventricular load or pulmonary arterial pressure, were detected.

Results. The ratio of left ventricular free wall plus septum to right ventricular weight significantly increased in hypoxia plus indomethacin-treated group. The medial thickness percentage of pulmonary arteries of < 100 μm and ≥100 μm in diameter from hypoxia plus indomethacin-treated group was higher than that from control or single treatment group. Vascular elastin area percentage and immunostaining density of eNOS from the combined-treated group were higher than other groups. The relative abundance of α-SMA, elastin, and eNOS and plasma BNP levels in hypoxia plus indomethacin-treated group also significantly increased compared with other groups.

Conclusions. Hypoxia and indomethacin had synergistic effect on fetal pulmonary vascular remodeling. This rat model induced by combined treatments can mimic human persistent pulmonary hypertension of the newborn.

Keywords:

• Persistent pulmonary hypertension of the newborn
• pulmonary vascular remodeling
• brain-type natriuretic peptide
• hypoxia
• indomethacin

Acknowledgements

We greatly thank Prof. Robert H. Lane and Kurt H. Albertine for reviewing this manuscript. We also thank Mr. Liu Di-Wen for his assistance during animal experiment. This work was supported by grant from National Natural Science Foundation of China (No. 30672265).