Published Online
on February 19, 2007

A more recent version of this article appeared on March 13, 2007

This Article Full Text (PDF) All Versions of this Article: 115/10/1260    most recent CIRCULATIONAHA.106.681718v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Said, S. I. Articles by Kort, S. Search for Related Content PubMed PubMed Citation Articles by Said, S. I. Articles by Kort, S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Pulmonary Hypertension Related Collections Clinical genetics Animal models of human disease Smooth muscle proliferation and differentiation Pulmonary circulation and disease Other Vascular biology

Submitted on December 1, 2006
Accepted on January 2, 2007

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, and 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.).

^* To whom correspondence should be addressed. E-mail: sami.i.said{at}stonybrook.edu.

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.

Key words: cardiovascular diseases • genetics • hypertension, pulmonary • pathology • peptides • remodeling • vasculature

This article has been cited by other articles:

				K. R. Stenmark, B. Meyrick, N. Galie, W. J. Mooi, and I. F. McMurtry Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure Am J Physiol Lung Cell Mol Physiol, December 1, 2009; 297(6): L1013 - L1032. [Abstract] [Full Text] [PDF]

				E. C. Dempsey, M. J. Wick, V. Karoor, E. J. Barr, D. W. Tallman, C. A. Wehling, S. J. Walchak, S. Laudi, M. Le, M. Oka, et al. Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia Am. J. Pathol., March 1, 2009; 174(3): 782 - 796. [Abstract] [Full Text] [PDF]

				H. H. Leuchte, C. Baezner, R. A. Baumgartner, D. Bevec, G. Bacher, C. Neurohr, and J. Behr Inhalation of vasoactive intestinal peptide in pulmonary hypertension Eur. Respir. J., November 1, 2008; 32(5): 1289 - 1294. [Abstract] [Full Text] [PDF]

				A. Shifren, A. G. Durmowicz, R. H. Knutsen, G. Faury, and R. P. Mecham Elastin insufficiency predisposes to elevated pulmonary circulatory pressures through changes in elastic artery structure J Appl Physiol, November 1, 2008; 105(5): 1610 - 1619. [Abstract] [Full Text] [PDF]

				K. Boutet, D. Montani, X. Jais, A. Yaici, O. Sitbon, G. Simonneau, and M. Humbert Review: Therapeutic advances in pulmonary arterial hypertension Therapeutic Advances in Respiratory Disease, August 1, 2008; 2(4): 249 - 265. [Abstract] [PDF]

				Y.-J. Lai, S. S. Pullamsetti, E. Dony, N. Weissmann, G. Butrous, G.-A. Banat, H. A. Ghofrani, W. Seeger, F. Grimminger, and R. T. Schermuly Role of the Prostanoid EP4 Receptor in Iloprost-mediated Vasodilatation in Pulmonary Hypertension Am. J. Respir. Crit. Care Med., July 15, 2008; 178(2): 188 - 196. [Abstract] [Full Text] [PDF]

				M. Humbert Update in Pulmonary Arterial Hypertension 2007 Am. J. Respir. Crit. Care Med., March 15, 2008; 177(6): 574 - 579. [Full Text] [PDF]

				E. Daley, C. Emson, C. Guignabert, R. de Waal Malefyt, J. Louten, V. P. Kurup, C. Hogaboam, L. Taraseviciene-Stewart, N. F. Voelkel, M. Rabinovitch, et al. Pulmonary arterial remodeling induced by a Th2 immune response J. Exp. Med., February 18, 2008; 205(2): 361 - 372. [Abstract] [Full Text] [PDF]

				S. A. Hamidi, S. Prabhakar, and S. I. Said Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion Eur. Respir. J., January 1, 2008; 31(1): 135 - 139. [Abstract] [Full Text] [PDF]

				M. Xu, O. Platoshyn, A. Makino, W. H. Dillmann, K. Akassoglou, C. V. Remillard, and J. X.-J. Yuan Characterization of agonist-induced vasoconstriction in mouse pulmonary artery Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H220 - H228. [Abstract] [Full Text] [PDF]