University College Dublin, School of Medicine and Medical Sciences, Belfield, Dublin 4, Ireland.
Circulation. 2012 Feb 21;125(7):920-30. doi: 10.1161/CIRCULATIONAHA.111.038125. Epub 2012 Jan 13.
Pulmonary hypertension occurs in chronic hypoxic lung diseases, significantly worsening morbidity and mortality. The important role of altered bone morphogenetic protein (BMP) signaling in pulmonary hypertension was first suspected after the identification of heterozygous BMP receptor mutations as the underlying defect in the rare heritable form of pulmonary arterial hypertension. Subsequently, it was demonstrated that BMP signaling was also reduced in common forms of pulmonary hypertension, including hypoxic pulmonary hypertension; however, the mechanism of this reduction has not previously been elucidated.
Expression of 2 BMP antagonists, gremlin 1 and gremlin 2, was higher in the lung than in other organs, and gremlin 1 was further increased in the walls of small intrapulmonary vessels of mice during the development of hypoxic pulmonary hypertension. Hypoxia stimulated gremlin secretion from human pulmonary microvascular endothelial cells in vitro, which inhibited endothelial BMP signaling and BMP-stimulated endothelial repair. Haplodeficiency of gremlin 1 augmented BMP signaling in the hypoxic mouse lung and reduced pulmonary vascular resistance by attenuating vascular remodeling. Furthermore, gremlin was increased in the walls of small intrapulmonary vessels in idiopathic pulmonary arterial hypertension and the rare heritable form of pulmonary arterial hypertension in a distribution suggesting endothelial localization.
These findings demonstrate a central role for increased gremlin in hypoxia-induced pulmonary vascular remodeling and the increased pulmonary vascular resistance in hypoxic pulmonary hypertension. High levels of basal gremlin expression in the lung may account for the unique vulnerability of the pulmonary circulation to heterozygous mutations of BMP type 2 receptor in pulmonary arterial hypertension.
肺动脉高压发生于慢性低氧性肺部疾病，显著增加发病率和死亡率。骨形态发生蛋白（BMP）信号改变在肺动脉高压中的重要作用，最初是在发现杂合 BMP 受体突变是罕见遗传性肺动脉高压的潜在缺陷后被怀疑的。随后，研究表明，BMP 信号也在常见形式的肺动脉高压中降低，包括低氧性肺动脉高压；然而，这种降低的机制尚未被阐明。
2 种 BMP 拮抗剂，gremlin 1 和 gremlin 2 的表达在肺部高于其他器官，并且在低氧性肺动脉高压发展过程中小肺内血管的壁中 gremlin 1 进一步增加。低氧在体外刺激人肺微血管内皮细胞分泌 gremlin，抑制内皮细胞 BMP 信号和 BMP 刺激的内皮修复。gremlin 1 的单等位基因缺失在低氧小鼠肺部增强了 BMP 信号，并通过减弱血管重塑来降低肺血管阻力。此外，在特发性肺动脉高压和罕见遗传性肺动脉高压中小肺内血管的壁中，gremlin 增加，分布提示内皮定位。
这些发现表明，增加的 gremlin 在低氧诱导的肺血管重塑和低氧性肺动脉高压中的肺血管阻力增加中起核心作用。肺中基础 gremlin 表达水平高可能是肺动脉高压中 BMP 类型 2 受体杂合突变导致肺循环易感性的独特原因。
