Am. J. Respir. Crit. Care Med., Volume 164, Number 2, July 2001, 314-318

Prostacyclin Receptor-dependent Modulation of Pulmonary Vascular Remodeling

YASUSHI HOSHIKAWA, NORBERT F. VOELKEL, TRACY L. GESELL, MARK D. MOORE, KENNETH G. MORRIS, LORI A. ALGER, SHUH NARUMIYA, and MARK W. GERACI

Division of Pulmonary Sciences and Critical Care Medicine, Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver, Colorado; and Department of Pharmacology, Kyoto University, Sakyo, Kyoto, Japan

Prostacyclin (PGI₂) reduces pulmonary vascular resistance and attenuates vascular smooth muscle cell proliferation through signal transduction following ligand binding to its receptor. Because patients with severe pulmonary hypertension have a reduced PGI₂ receptor (PGI-R) expression in the remodeled pulmonary arterial smooth muscle, we hypothesized that pulmonary vascular remodeling may be modified PGI-R dependently. To test this hypothesis, PGI-R knockout (KO) and wild-type (WT) mice were subjected to a simulated altitude of 17,000 ft or Denver altitude for 3 wk, and right ventricular pressure and lung histology were assessed. The PGI-R KO mice developed more severe pulmonary hypertension and vascular remodeling after chronic hypoxic exposure when compared to the WT mice. Our results indicate that PGI₂ and its receptor play an important role in the regulation of hypoxia-induced pulmonary vascular remodeling, and that the absence of a functional receptor worsens pulmonary hypertension.

Key Words: knockout mice; prostacyclin receptor; pulmonary hypertension; chronic hypoxia

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