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A3757 - Endothelial Gremlin1 Plays an Important Role in the Homeostasis of the Pulmonary Circulation
Author Block: S. C. Rowan, J. Cornwell, L. Piouceau, P. McLoughlin; University College Dublin, Dublin, Ireland.
Introduction
The development of pulmonary hypertension (PH) in those suffering from chronic lung disease is independently linked to a poor prognosis. We have previously reported that haploinsufficiency of the bone morphogenetic protein antagonist Gremlin1 (Grem1+/-) protects against the development of hypoxic PH in murine models (Cahill et al. 2012). Gremlin1 is produced by at least three cellular sources in the lung: macrophages, endothelial cells and type 2 pneumocytes. Previous in vitro experiments suggest that hypoxic pulmonary endothelial cells secrete, and are major sources of, Gremlin1 in the PH lung. To investigate the contribution of endothelial derived Gremlin1 to the pathogenesis of hypoxic PH we examined the effect of endothelial Gremlin1 deletion in a novel inducible endothelial-specific Gremlin1 knockout mouse model.
Methods
Endothelial-specific Gremlin1 deletion was induced by feeding adult Gremlin1LoxP/LoxP.Ve.Cadherin.Cre mice (GremF/F.Cre) a tamoxifen diet for four weeks followed by a two week washout. Controls were feed a normal diet for the duration. Mice were then exposed to normoxic or hypoxic (FIO2=0.10) conditions for three weeks. Following this, mice were deeply anaesthetised, anti-coagulated and exsanguinated. Pulmonary haemodynamics were assessed using an isolated perfused lung preparation.
Results
Endothelial Gremlin1 deletion in tamoxifen fed Grem F/F.Cre lung tissue was confirmed by end-point PCR. Hypoxia induced increases in haematocrit were similar in GremF/F.Cre mice fed either a normal or tamoxifen diet, confirming a normal systemic response to hypoxia. RV:LV+S was increased in both normoxic and hypoxic GremF/F.Cre mice fed a tamoxifen diet in comparison to controls fed a normal diet. Pulmonary vascular resistance was significantly elevated in both normoxic and hypoxic tamoxifen fed GremF/F.Cre mice in comparison to normal diet controls. However, the hypoxia induced increase in pulmonary vascular resistance was unchanged in the tamoxifen fed mice. Histological examination of lung structure from GremF/F.Cre fed a tamoxifen diet suggested loss of alveolar walls compatible with early emphysema when compared to controls fed a normal diet.
Conclusion
These results suggest that endothelial Gremlin1 plays a crucial role in maintaining normal pulmonary vascular homeostasis. Cellular sources other than the endothelium are likely to contribute to the development of PH. This research was generously funded by Science Foundation Ireland and by the Irish government through the Programme for Research in Third Level Institutions.*SCR and JC contributed to this work equally.