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Background: We hypothesised that the potential protective effects of endothelial ET_B are important in limiting pulmonary vascular muscularisation, vasoconstriction and the development of pulmonary arterial hypertension in response to hypoxia. Methods: EC-specific ET_B knockout mice (EC ET_B^–/–) and control mice (ET_B^f/f) were subjected to hypobaric hypoxic (10% FiO₂) 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 ET_B^–/– (23.7 ± 1.7 mm Hg) and ET_B^f/f mice (20.2 ± 1.5 mm Hg). Hypoxia induced an exaggerated increase in right ventricular pressure in EC ET_B^–/– 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 ET_B^f/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 ET_B^–/– 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.

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