Pulmonary prostacyclin, synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension

Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway leading to prostacyclin (PGI(2)) production. Patients with severe pulmonary hypertension have a PGIS deficiency of their precapillary vessels , but the importance of this deficiency for lung vascular remodeling remain s unclear. We hypothesized that selective pulmonary overexpression of PGIS may prevent the development of pulmonary hypertension. To study this hypoth esis, transgenic mice were created with selective pulmonary PGIS overexpres sion using a construct of the 3.7-kb human surfactant protein-C (SP-C) prom oter and the rat PGIS cDNA. Transgenic mice (Tg(+)) and nontransgenic litte rmates (Tg(-)) were subjected to a simulated altitude of 17,000 ft for 5 we eks, and right ventricular systolic pressure (RVSP) was measured. Histology was performed on the lungs. The Tg(+) mice produced 2-fold more pulmonary 6-keto prostaglandin F-1 alpha(PGF(1 alpha)) levels than did Tg(-) mice. Af ter exposure to chronic hypobaric hypoxia, Tg(+) mice have lower RVSP than do Tg(-) mice. Histologic examination of the lungs revealed nearly normal a rteriolar vessels in the Tg(+) mice in comparison with vessel wall hypertro phy in the Tg(-) mice. These studies demonstrate that Tg(+) mice were prote cted from the development of pulmonary hypertension after exposure to chron ic hypobaric hypoxia. We conclude that PGIS plays a major role in modifying the pulmonary vascular response to chronic hypoxia. This has important imp lications for the pathogenesis and treatment of severe pulmonary hypertensi on.