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This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/L1182    most recent 00020.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Reynolds, A. M. Articles by Reynolds, P. N. Search for Related Content PubMed PubMed Citation Articles by Reynolds, A. M. Articles by Reynolds, P. N.

Bone morphogenetic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension

¹Lung Research Laboratory, Royal Adelaide Hospital, ²Hanson Institute and ³University of Adelaide, Adelaide, South Australia, Australia; ⁴Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois; ⁵Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama; and ⁶Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom

Submitted 14 January 2006 ; accepted in final form 26 January 2007

Idiopathic pulmonary arterial hypertension (PAH) is characterized by proliferation of pulmonary vascular endothelial and smooth muscle cells causing increased vascular resistance and right heart failure. Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) are believed to cause the familial form of the disease. Reduced expression of BMPR2 is also noted in secondary PAH. Recent advances in the therapy of PAH have improved quality of life and survival, but many patients continue to do poorly. The possibility of treating PAH via improving BMPR2 signaling is thus a rational consideration. Such an approach could be synergistic with or additive to current treatments. We developed adenoviral vectors containing the BMPR2 gene. Transfection of cells in vitro resulted in upregulation of SMAD signaling and reduced cell proliferation. Targeted delivery of vector to the pulmonary vascular endothelium of rats substantially reduced the pulmonary hypertensive response to chronic hypoxia, as reflected by reductions in pulmonary artery and right ventricular pressures, right ventricular hypertrophy, and muscularization of distal pulmonary arterioles. These data provide further evidence for a role for BMPR2 in PAH and provide a rationale for the development of therapies aimed at improving BMPR2 signaling.

hypoxia; growth substances; endothelium