Rational – Chronic lung diseases, including chronic obstructive pulmonary diseases are among the leading causes of mortality worldwide. The pathogenesis of chronic lung disease is not fully understood, however chronic hypoxia is commonly seen in this setting. Our laboratory has recently demonstrated hypoxia-induced angiogenesis in the adult rat and mouse lungs. Placental growth factor (PlGF), a homologue of VEGF, is known to play a role in systemic angiogenesis, however little is known of its role in the pulmonary vasculature. Elucidating the distinct roles of the VEGF family particularly PlGF in hypoxia-induced angiogenesis could provide possible therapeutic strategies for treatment of such lung diseases where tissue loss is apparent. Methods – Adult male wild-type and placental growth factor knockout (PlGF-/-) mice were exposed to hypoxic (FiO2 0.10) or normoxic (FiO2 0.21) conditions for 3 weeks. Following the exposure period, the animals were deeply anesthetised (60mg.kg-1 sodium pentobarbitone, intraperitoneally) and killed by exanguination. 1) Alterations of the different growth factors (VEGF-A and VEGF-D) and their receptors (soluble VEGFR-1, soluble VEGFR-2, neuropilin-1 and membrane bound VEGFR-2) at protein level were assessed using ELISA assays and western blot analysis. 2) Isolated, ventilated perfused preparation was used to assess pulmonary vascular resistance and vascular permeability. 3) Lungs were removed post mortem and perfused and fixed at standard pressures for structural analysis of vascular and airway parameters using stereological methods. Results – We have demonstrated differential regulation of the VEGF family members in response to hypoxia in PlGF-/- mice. Loss of PlGF resulted in a significant increase in pulmonary vascular resistance indicating pulmonary hypertension compared to Wt mice. Increased vascular permeability was observed in PlGF-/- compared to Wt mice following 24hrs of hypoxic conditions indicating increased vascular leak. PlGF-/- mice also have significantly attenuated alveolar epithelial surface area compared to Wt controls. Conclusion – VEGF family members were differentially regulated in PlGF-/- mice suggesting a potential compensatory mechanism in the adult lung. PlGF-/- mice demonstrated worse pulmonary vascular resistance, reduced epithelial surface area and increased vessel leak compared to wild-type mice suggesting an important role for PlGF in maintenance of normal vascular function. Taken together these data suggest a potentially important therapeutic target for the treatment of hypoxic lung disease.