Endothelial ETB Limits Vascular Remodelling and Development of Pulmonary Hypertension during Hypoxia

Background: We hypothesised that the potential protective effects of endothelial ETB are important in limiting pulmonary vascular muscularisation, vasoconstriction and the development of pulmonary arterial hypertension in response to hypoxia. Methods: EC-specific ETB knockout mice (EC ETB-/-) and control mice (ETBf/f) were subjected to hypobaric hypoxic (10% FiO(2)) or normoxic conditions for 14 days before assessment of right ventricular pressure and pulmonary vascular morphology and function. Results: During normoxia, no difference in right ventricular pressure was detected between EC ETB-/- (23.7 +/- 1.7 mm Hg) and ETBf/f mice (20.2 +/- 1.5 mm Hg). Hypoxia induced an exaggerated increase in right ventricular pressure in EC ETB-/- mice (34.4 +/- 1.2 mm Hg vs. 24.6 +/- 1.4 mm Hg), accompanied by an increase in right ventricular mass. No effect was observed in ETBf/f mice. Endothelin-1 constricted pulmonary arteries from both groups, although maximum response was similar irrespective of inspired oxygen or genotype. Hypoxia increased the percentage of muscularised vessels in both groups of mice, but the percentage increase was significantly greater in EC ETB-/- mice. Conclusions: The potential protective effects of endothelial ET B are important in limiting pulmonary vascular muscularisation and the development of pulmonary arterial hypertension in response to hypoxia. Copyright (C) 2009 S. Karger AG, Basel