Heart failure is a cause of pulmonary vasoconstriction and remodelling, leading to pulmonary hypertension and decreased survival. The pathobiology of pulmonary hypertension on heart failure remains incompletely understood. We investigated pulmonary vascular function and signalling molecules in a previously validated canine overpacing protocol with a stepwise increase of stimulation frequencies over a period of 7 weeks to induce severe heart failure. Eight beagle dogs with overpacing-induced heart failure underwent hemodynamic measurements and post-mortem pulmonary arterial morphometry and reactivity, and real-time quantitative PCR on lung arteries for mRNA determinations of components of endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), nitric oxide (NO), serotonin and angiogenetic pathways. Overpacing was associated with a decrease in cardiac output and an increase in pulmonary vascular pressures. However, there were no changes in pulmonary vascular resistance or in arteriolar medial thickness. There were increased expressions of ET-1, ETB and VEGF. In vitro pulmonary arteries showed decreased relaxation and increased reactivity, while mammary arteries were not different from controls. Early stage pulmonary hypertension on heart failure is characterized by altered vasoreactivity and increased ET-1/ETB and VEGF signalling