Chronic exposure to hypoxia such as at high altitude causes pulmonary hypertension (PH). PH is characterised by vasoconstriction, remodelling of the pulmonary vessels and sustained increases in pulmonary vascular resistance. The bone morphogenetic proteins (BMPs) play a vital role in maintaining normal pulmonary vascular homeostasis. Attenuated BMP signaling has been found in many common forms of PH including hypoxic PH. Recent work in our laboratory indicated that lung specific, hypoxia induced, upregulation of expression of the BMP antagonist gremlin1 (Grem1) plays a central role in the pathogenesis of hypoxic PH (1). Grem1 may act as a VEGFR2 agonist leading to VEFR2 dependent angiogenic responses (2). VEGFR2 activation increases eNOS production of NO, which has essential anti-remodelling and pro-angiogenic roles in the lung. However, through its BMP blocking action a hypoxia induced increase in grem1 could lead to a reduction in eNOS expression and activity (3). Given these potentially antagonist roles we examined the effect of heterozygous loss of grem1 on angiogenesis and eNOS expression and activity in the hypoxic mouse. Wild-type (WT) and gremlin heterozygous knockout mice (Grem+/-) were exposed to either normoxia (FIO2=0.21) or hypoxia (FIO2=0.10) for 2 days or 3 weeks. Following exposure they were anaesthetized (sodium pentobarbital 60mg.kg-1, i.p.) and exsanguinated. The lungs were removed and the resistance assessed using an isolated ventilated perfused lung preparation (n=17-20 per group). Separate groups of lungs (n=10-12 per group) were fixed for stereological assessment of the pulmonary vasculature as previously described (4). eNOS expression and NO activity were measured by western blot (n= 8 per group). In agreement with our previous work Grem+/- mice showed an attenuated increase in PVR (2.92±0.08 mmHg.ml.min-1) that was significantly lower (P<0.01, t-test) than that observed in the wild type mice (3.31±0.06 mmHg.ml.min-1). eNOS expression and NO activity were significantly elevated (P<0.01, Mann Whitney U) in 2 day hypoxic Grem+/- mice in comparison to WT controls. Quantitative stereology demonstrated similar significant (P<0.05, t-test) hypoxia induced increases in epithelial and endothelial surface area, consistent with hypoxia-induced angiogenesis, in both hypoxic WT and Grem+/- mouse lungs. These data suggest that the loss of grem1 protects against hypoxic PH, at least in part, by increasing NO expression and activity. The heterozygous loss of grem1 did not lead to a reduction in hypoxia-induced angiogenesis. These finding suggest that gremlin does not have a significant VEGFR agonist activity in the hypoxic lung but primarily acts to antagonise BMP signaling.