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C ytosolic phospholipase A₂ (cPLA₂) releases arachidonic acid (AA) from phospholipids in cell membranes. To assess the role of cPLA₂ in hypoxic pulmonary vasoconstriction (HPV), we measured the increase in left lung pulmonary vascular resistance (LPVR) before and during hypoxia produced by left main stem bronchus occlusion (LMBO) in mice with and without a targeted deletion of the PLA2g4a gene that encodes cPLA_2α. LMBO increased LPVR in cPLA_2α^+/+ mice but not in cPLA_2α^–/– mice. cPLA_2α^+/+ mice were better able to maintain systemic oxygenation during LMBO than were cPLA_2α^–/– mice. Administration of a cPLA₂ inhibitor, arachidonyl trifluoromethyl ketone, blocked the LMBO-induced increase in LPVR in wild-type mice, while exogenous AA restored HPV in cPLA_2α^–/– mice. Intravenous angiotensin II infusion increased PVR similarly in cPLA_2α^+/+ and cPLA_2α^–/– mice. Inhibitors of cyclooxygenase or nitric oxide synthase restored HPV in cPLA_2α^–/– mice. Breathing 10% oxygen for 3 weeks produced less right ventricular hypertrophy in cPLA_2α^–/– than in cPLA_2α^+/+ mice, but restored HPV in cPLA_2α^–/– mice despite the continued absence of cPLA₂ activity. These results indicate that cPLA₂ contributes to the murine pulmonary vasoconstrictor response to hypoxia. Augmenting pulmonary vascular tone restores HPV in the absence of cPLA₂ activity.