Abstract
During early postnatal life, the lung undergoes profound adaptive processes as a result of taking on the function of gas exchange and neonates may be particularly vulnerable to developing pulmonary hypertension. The bone morphogenetic protein (BMP) antagonist, Gremlin 1 (GREM1) has been recently suggested to contribute to the development of pulmonary arterial hypertension (Cahill E. et al., Circulation 2012; 125: 920-30). The aim of this study was to analyze the role of GREM1 during pulmonary postnatal development and upon hypoxic challenge in the neonatal period.
C57/Bl6 newborn mice were randomly placed into normoxic (21% O2) or normobaric hypoxic (13% O2) chambers for 2 weeks. Adult mice (10 weeks-old) were used for comparison. Vascular reactivity was assessed using intrapulmonary arteries mounted into isometric wire myographs and lung mRNA levels were analysed by real time PCR.
Lung mRNA levels of the BMP receptor BMPR2 increased 1.5-fold with postnatal age alongside a 4-fold decrease in the BMP antagonist GREM1. Exposure to chronic hypoxia during the first 2 weeks of life decreased the expression levels of BMPRII by 1.4-fold and upregulated GREM1 by 2.3-fold. In addition, exposure of 2-weeks-old PA to GREM1 (100ng/mL) for 20 hours significantly increased the contractile responses to high potassium and to the thromboxane A2 mimetic U46619.
These findings suggest that a maturational decrease in the expression of the BMP antagonist GREM1 occurs during postnatal development and may contribute to the regulation of pulmonary vascular tone.
Supported by Spanish MINECO (2011-28150) and ISCIII (CP12/03304).
- © 2014 ERS