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(Circulation. 2007;115:1260-1268.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Moderate Pulmonary Arterial Hypertension in Male Mice Lacking the Vasoactive Intestinal Peptide Gene

Sami I. Said, MD; Sayyed A. Hamidi, MD; Kathleen G. Dickman, PhD; Anthony M. Szema, MD; Sergey Lyubsky, MD; Richard Z. Lin, MD; Ya-Ping Jiang, MD; John J. Chen, PhD; James A. Waschek, PhD; Smadar Kort, MD

From the Departments of Medicine (S.I.S., S.A.H., K.G.D., A.M.S., R.Z.L., Y.-P.J., S.K.), Pathology (S.L.), and Preventive Medicine (J.J.C.), State University of New York at Stony Brook; Department of Veterans Affairs Medical Center, Northport, NY (S.I.S., S.A.H., K.G.D., A.M.S., S.L., R.Z.L.); and Department of Psychiatry, University of California, Los Angeles, Los Angeles (J.A.W.).

Correspondence to Sami I. Said, Pulmonary and Critical Care Medicine, SUNY Health Sciences Center, T–17–040, Stony Brook, NY 11784. E-mail sami.i.said{at}stonybrook.edu

Received December 1, 2006; accepted January 2, 2007.

Background— Vasoactive intestinal peptide (VIP), a pulmonary vasodilator and inhibitor of vascular smooth muscle proliferation, has been reported absent in pulmonary arteries from patients with idiopathic pulmonary arterial hypertension (PAH). We have tested the hypothesis that targeted deletion of the VIP gene may lead to PAH with pulmonary vascular remodeling.

Methods and Results— We examined VIP knockout (VIP^–/–) mice for evidence of PAH, right ventricular (RV) hypertrophy, and pulmonary vascular remodeling. Relative to wild-type control mice, VIP^–/– mice showed moderate RV hypertension, RV hypertrophy confirmed by increased ratio of RV to left ventricle plus septum weight, and enlarged, thickened pulmonary artery and smaller branches with increased muscularization and narrowed lumen. Lung sections also showed perivascular inflammatory cell infiltrates. No systemic hypertension and no arterial hypoxemia existed to explain the PAH. The condition was associated with increased mortality. Both the vascular remodeling and RV remodeling were attenuated after a 4-week treatment with VIP.

Conclusions— Deletion of the VIP gene leads to spontaneous expression of moderately severe PAH in mice during air breathing. Although not an exact model of idiopathic PAH, the VIP^–/– mouse should be useful for studying molecular mechanisms of PAH and evaluating potential therapeutic agents. VIP replacement therapy holds promise for the treatment of PAH, and mutations of the VIP gene may be a factor in the pathogenesis of idiopathic PAH.

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