Tissue responses to ischemia species (ROSs; ref. 22); because of regional decreases in blood flow, chronic hypoxic vasoconstriction can lead to ischemia/reperfusion injury, inducing inflammation and causing the accumulation of ROSs in the lung parenchyma (23). Such injury may be restricted to the initial stage of chronic hypoxia, or occur in situations of intermittent hypoxia/hypoxemia, as seen in the sleep apnea syndrome. Sources of ROSs in the hypoxemic lung include endothelium-derived xanthine-oxidase, cyclooxygenases, lipoxygenases, endothelial NO synthase (eNOS), VSMC-derived NADH oxidase, and activated macrophages. In aggregate, ROSs may deplete lung tissue NO and activate both cell proliferation and cell death (24). The complex and multifactorial response to this single physicochemical stimulus, chronic hypoxia, makes it difficult to dissect the effects of potentially useful therapeutic agents. Thus, calcium-entry blockers are believed to prevent development of chronic hypoxiainduced pulmonary hypertension by inhibiting hypoxic vasoconstriction (25), but other drug actions are possible. Chronic treatment of rats with a platelet-activating factor antagonist, which does not affect pulmonary vascular constriction, decreases chronic hypoxia-induced pulmonary vascular remodeling and decreases the pulmonary hypertension (26). It should be noted that the increase in pulmonary artery pressure seen during acute hypoxic exposure results from vasoconstriction, whereas the pulmonary hypertension following chronic hypoxia can be explained to a large extent by the structural alteration of the small pulmonary arteries and may occur even in the absence of vasoconstriction. Thus, treatment of rats with anti-VEGF antibodies may not directly induce vasoconstriction, either acutely or chronically, but long-term exposure to this antibody enhances hypoxia-induced pulmonary hypertension (27), associated with loss of pulmonary vasodilation and also increased vascular remodeling, likely because of the decreased production of prostacyclin (28) and NO (29).