Gremlin plays a key role in the pathogenesis of pulmonary hypertension.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

The pathophysiological basis of chronic hypoxic pulmonary hypertension in the mouse: vasoconstrictor and structural mechanisms contribute equally.

Chronic hypoxic pulmonary hypertension is characterized by a sustained increase in pulmonary arterial pressure due to abnormally elevated pulmonary vascular resistance. This increased vascular resistance was previously thought to be due largely to changes in the structure of the pulmonary vasculature, i.e. lumen narrowing due to wall hypertrophy and loss of vessels. Recently, this model has been challenged by the demonstration that hypoxic pulmonary hypertension in the rat is caused almost completely by sustained vasoconstriction. The contribution of this vasocontriction to hypoxic pulmonary hypertension has not been examined directly in other species. We exposed groups of mice to hypoxia (10% O(2)) or normoxia for 3 weeks, following which the lungs were removed post mortem, and vascular resistance was measured in an isolated, ventilated, perfused preparation. Mean pulmonary vascular resistance was significantly increased in hypoxic compared with control normoxic lungs. The rho kinase inhibitor Y27635 (10(-4)m) (Tocris Bioscience, Bristol, United Kingdom.) significantly reduced the mean (± SEM) hypoxia induced increase by 45.4 (10.8)%, implying that structural vascular changes acounted for the remainder of the hypoxic increase. Stereological quantification showed a significant reduction in the mean lumen diameter of the fully relaxed vessels in hypoxic lungs compared with normoxic control lungs; there was no intra-acinar vessel loss. Thus, in contrast to the rat, hypoxic pulmonary hypertension in the mouse is due to two mechanisms contributing equally: sustained vasoconstriction and structural lumen narrowing of intra-acinar vessels. These important species diferences must be considered when using genetically mutated mice to investigate the mechanisms underlying pulmonary hypertension.

Role of gremlin in the lung: development and disease.

Gremlin is an extracellular glycoprotein that was first identified over a decade ago through its important role in embryonic development, in which it acts as an antagonist of bone morphogenetic protein actions. It plays a critical role in the development of normal airways and the pulmonary circulation in the embryo. More recently, considerable evidence has been presented for a role for gremlin in the pathogenesis of lung diseases, particularly pulmonary hypertension and idiopathic pulmonary fibrosis. The purpose of this article is to review this evidence, consider the potential mechanisms and multicellular actions by which gremlin contributes to disease pathogenesis, and suggest future avenues of research.

Lung-selective gene responses to alveolar hypoxia: potential role for the bone morphogenetic antagonist gremlin in pulmonary hypertension.

Pulmonary hypoxia is a common complication of chronic lung diseases leading to the development of pulmonary hypertension. The underlying sustained increase in vascular resistance in hypoxia is a response unique to the lung. Thus we hypothesized that there are genes for which expression is altered selectively in the lung in response to alveolar hypoxia. Using a novel subtractive array strategy, we compared gene responses to hypoxia in primary human pulmonary microvascular endothelial cells (HMVEC-L) with those in cardiac microvascular endothelium and identified 90 genes (forming 9 clusters) differentially regulated in the lung endothelium. From one cluster, we confirmed that the bone morphogenetic protein (BMP) antagonist, gremlin 1, was upregulated in the hypoxic murine lung in vivo but was unchanged in five systemic organs. We also demonstrated that gremlin protein was significantly increased by hypoxia in vivo and inhibited HMVEC-L responses to BMP stimulation in vitro. Furthermore, significant upregulation of gremlin was measured in lungs of patients with pulmonary hypertensive disease. From a second cluster, we showed that CXC receptor 7, a receptor for the proangiogenic chemokine CXCL12, was selectively upregulated in the hypoxic lung in vivo, confirming that our subtractive strategy had successfully identified a second lung-selective hypoxia-responsive gene. We conclude that hypoxia, typical of that encountered in pulmonary disease, causes lung-specific alterations in gene expression. This gives new insights into the mechanisms of pulmonary hypertension and vascular loss in chronic lung disease and identifies gremlin 1 as a potentially important mediator of vascular changes in hypoxic pulmonary hypertension.