Here, we tested the hypothesis that animals with severe pulmonary arterial hypertension (PAH) display increased sensitivity to vascular permeability induced by activation of store operated calcium entry. To test this hypothesis, wild type and TRPC4 knockout Fischer 344 rats were given a single injection of Semaxanib (SU5416; 20 mg/kg) followed by three weeks of exposure to hypoxia (10% oxygen) and a return to normoxia (21% oxygen) for an additional two to three weeks. This Semaxanib/hypoxia/normoxia (i.e. SU5416/hypoxia/normoxia) treatment caused PAH, as evidenced by development of right ventricular hypertrophy, pulmonary artery medial hypertrophy, and occlusive lesions within precapillary arterioles. Pulmonary artery pressure was increased five-fold in Semaxanib/hypoxia/normoxia-treated animals compared to untreated, Semaxanib-treated, and hypoxia treated controls, determined by isolated perfused lung studies. Thapsigargin induced a dose-dependent increase in permeability that was dependent upon TRPC4 in the normotensive perfused lung. This increase in permeability was accentuated in PAH, but not in Semaxanib- or hypoxia-treated, lungs. Fluid accumulated in large perivascular cuffs, and although alveolar fluid accumulation was not seen in histological sections, Evan's blue dye conjugated to albumin was present in bronchoalveolar lavage fluid of hypertensive, but not normotensive, lungs. Thus, PAH is accompanied by a TRPC4-dependent increase in the sensitivity to edemagenic agents that activate store operated calcium entry.